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The heffter review of psychedelic research, vol 1 (1998)
WHAT IS THE HEFFTER RESEARCH INSTITUTE?
Given the paramount importance of the nature of the human mind to global existence, it is curious -- and unsettling -- to realize how little we know about it. The mind is the source of all discovery and invention, yet therelationship between brain and mind remains a mystery. Since our minds are our only means of solving theproblems we face on this planet, understanding how the mind works and the nature of its relationship to the brainis an urgent and compelling priority.
Psychedelics have the unique ability to transform fundamentally the very functions that we consider uniquely human: the way we think, feel, communicate, and solve problems. They shift our cognitive and symboliccapacities, our aesthetic and spiritual sensibilities, and our linguistic and imaginative abilities; the very kinds ofbrain functions that constitute the fabric of what we experience as mind. Because psychedelic agents are similar tonatural substances already present in the human brain, the careful study of their effects upon brain function andexperiences provides access to primary states of brain and mind and the connections between them. For thesereasons, research with psychedelic substances offers an unparalleled opportunity for understanding the relationshipof brain to mind in ways not possible using other methods. Indeed, it is the thesis of the Heffter Research Institutethat these substances represent an essential technology for this investigation. From the chemical and neurologicallevel, to the psychological and spiritual, psychedelic research is a complex and difficult area of exploration.
Nevertheless, the time has come to apply our scientific sophistication to explore the powerful influences ofpsychedelics on the brain and mind.
For millennia, psychedelics played essential roles in the culture and spiritual practices of advanced civilizations such as the Mayans, Greeks, and Indo-Aryans. These substances hold similar importance today inmany traditional non-Western societies. We are at an historic moment. Old social orders are changing rapidly.
Economic powers are restructuring for the future. There is widespread popular interest in the brain and mind asnever before. Interest in research with psychedelics seems to be growing, and yet organized financial support forthis work is on the wane. The Heffter Research Institute is uniquely poised to be a key player in the revival ofpsychedelic research.
The mission of the Heffter Research Institute is to conduct research of the highest scientific quality with psychedelic substances in order to contribute to a greater understanding of the mind, leading to the improvement ofthe human condition, and the alleviation of suffering. This mission has already begun to attract scientists andresearchers of the highest caliber. The information and new knowledge gained will be disseminated to the medicaland scientific communities.
The Heffter Research Institute was incorporated in New Mexico in 1993 as a non-profit, 501(c)(3) organization in the belief that such research was not only viable but critically important. The Institute is namedafter Dr. Arthur Heffter, a turn-of-the century German research pharmacologist who discovered that mescaline wasthe principal psychoactive component in the peyote cactus.
The current political and intellectual climate offers new opportunities to reopen avenues of research that have been extremely difficult, if not impossible, to pursue in the past within conventional frameworks.
Government agencies will provide support to legitimate researchers of psychedelic agents, as the Institute Founderscan testify from long periods of research funding. Nevertheless, when it comes to extending the investigationsfrom animal models to human subjects, or to testing hypotheses that the effects of psychedelics may in certaincircumstances be beneficial rather than entirely detrimental, the government's role as a supporter of research hasbeen insufficient.
In order for truly uncompromised and creative research in the field of psychedelic neuropsychopharma- cology to have any hope of fulfilling its promise, it must be pursued from within the context of a research institutewhose operations and research programs are independent of government funding. The Heffter Research Institutewill neither condemn psychedelic drugs nor advocate their uncontrolled use. The sole position of the Institute inthis regard will be that psychedelic agents, utilized in thoughtfully designed and carefully conducted scientificexperiments, can be used to further the understanding of the mind.
The Heffter Research Institute will provide support, facilities, and opportunities to conduct both basic and clinical scientific research on psychedelic drugs that is legitimate and scientifically sound. The Institute is basedon the belief that such investigations hold great potential for producing genuine breakthroughs in theunderstanding of the human mind. The Founders intend that the Heffter Research Institute will be an enduringinstitution in the service of humankind.
The general objectives of The Heffter Institute include: • Developing knowledge regarding, and standards of practice for, the appropriate and safe use of psychedelic drugs in a medical context.
• Conducting basic chemical, pharmacological, and neurobiological investigations on psychedelic substances and their mechanisms of action.
• Conducting ethnopharmacological investigations designed to clarify our understanding of the role played by psychoactive plants in the religious, medical, and social institutions of other cultures.
• Conducting phytochemical and pharmacological investigations of plants and other naturally occurring materials, designed to discover, isolate, and characterize novel natural products withpsychedelic or other types of psychoactivity.
• Publishing scientific reports, earning grants and awards; organizing and sponsoring scientific conferences to present research results, and providing a forum for discussions of the appropriatemedical and scientific uses of psychedelic drugs.
• Conducting clinical research studies to investigate potential therapeutic applications of psychedelic • Informing the scientific and medical communities about the issues of safety, adverse effects, and therapeutic potentials related to psychedelic drug use in a medical context.
BE A PARTNER IN THE INSTITUTE'S PROGRESS
The Heffter Research Institute invites the support of those who wish to help realize its unique and valuable mission. Those individuals, corporations, and foundations, having the vision and commitment to help sponsor thisresearch enterprise, do so knowing that their contribution to the Institute and to the field of medicine is a criticallyimportant one.
Gifts for research, operating support, and capital funds are welcomed. In addition to gifts of cash, the Institute accepts gifts of securities as well as planned gifts and bequests. The Institute will work with a prospectivedonor to help realize the fullest tax advantage possible.
The Heffter Research Institute's Board of Directors has embarked upon an ambitious course. At this initial stage, research and start-up funds are needed to carry out our mission. Significant contributions will beneeded to reach the Institute's short and long-term goals. Potential donors are invited to contact the Institute at 330Garfield, Suite 301 Santa Fe, NM 87501, to explore our World Wide Web site at http://www.heffter.org, or tocontact George Greer, M.D., by telephone: (505) 982-0312, Fax: (505) 992-8260, or INTERNET(firstname.lastname@example.org), to explore how they might wish to participate in this idea whose time has come.
The Heffter Review of Psychedelic Research
Volume 1, 1998
Editor: David E. Nichols, Ph.D.
Published by: The Heffter Research Institute330 Garfield, Suite 301Santa Fe, NM 87501www.heffter.org Cover Art: Genesis I, Benini, 1994, by permission of the artistCover design by Mark Plummer List of Contributors
Callaway, Jace C., Ph.D., Department of Pharmacology and Toxicology, University of Kupio,Kupio, Finland Carter, Thomas J., Ph.D., Department of Computer Science and Cognitive Studies, CaliforniaState University, Turlock, California Geyer, Mark A., Ph.D., Dept of Psychiatry, School of Medicine, University of California at SanDiego, La Jolla, California Gouzoulis-Mayfrank, Euphrosyne, M.D., Psychiatric Department of the Technical University(RWTH), D-52074 Aachen, Germany Grinenko, A. Ya, M.D., Ph.D., Research Laboratory, Leningrad Regional Dispensary ofNarcology, Leningrad Region, Russia Grob, Charles S., M.D., Dept of Psychiatry, Harbor-UCLA Medical Center, Torrance, California90509 Hermle, Leo, M.D., Psychiatric and Neurological Hospital "Christophsbad" Faurndauerstrasse 6-28, D-73035 Göppingen, Germany Krupitsky, Evgeny M., M.D., Ph.D., Research Laboratory, Leningrad Regional Dispensary ofNarcology, Leningrad Region, Russia McKenna, Dennis J., Ph.D., P.O. Box 224, Marine on St. Croix, Minnesota 55047 Myers, Lin S., Ph.D., Departments of Psychology, Computer Science and Cognitive Studies,California State University, Turlock, California Nichols, David E., Ph.D., Dept of Medicinal Chemistry and Molecular Pharmacology, School ofPharmacy and Pharmacal Sciences, Purdue University, W. Lafayette, Indiana 47907 Schultes, Richard Evans, Ph.D., Director Emeritus, Harvard Botanical Museum, Cambridge,Massachusetts Vollenweider, Franz X., M.D., Program on neurobiology, University of Zurich Medical Faculty,Psychiatric University Hospital, Research Department, Zurich, Switzerland Walsh, Roger, M.D., Department of Psychiatry and Human Behavior, College of Medicine,University of California at Irvine, Irvine, California Watkins, Shelly S., M.A., Department of Neuropharmacology, The Scripps Research Institute, LaJolla, California.
There has been an extensive polarization of both political and public opinion over the last ten years in the area of drug use. The phrase "drug abuse" has been promoted into the role of a metaphorfor the problems in our society, and it has become the straw man for their solution. If we could winthe "war on drugs" we would have no more problems with crime (or poverty, or racism, or streetgangs, or illiteracy) and our social system would again become healthy and stable. The blaming of allof our problems on the drug abusers of today is a chilling parallel to the assigned role of the Jews asthe target problem in Germany, in the mid-30's. It is as if there are two opposite camps, the drugwarriors and the legalizers. If you were to speak against one, you would be branded a member of theother. Neither statesmen nor politicians can dare voice any rationality in these areas of controversyas neither chose to be branded as a spokesman for the other side. Quite literally, the arena hasbecome a, "If you are not for us, you are against us," dichotomy, and there is less and less dialogoccurring. At the Congressional level, any new law that mentions the word "drug' in the definition ofa crime or the increasing of a penalty against crime, is rarely opposed. Any counter arguer would beseen as "soft on drugs," and would fear losing voter support. In recent years, even the Supreme Courthas voted more and more frequently on the side of perceived public response to their decision, ratherthan on the Constitutional fine print, when an appeal being considered has involved the word, "drug." Even simple phrases have become loaded sound-bites. A convention on harm reduction in the area of drug use or the potential medical uses of marijuana will be seen by law enforcement and thepolitical establishment as a gathering of drug legalizers, and they will condemn it from a distance. Aconvention on international precursor control or the neurological risks associated with the use ofillegal drugs will be seen by the medical and academic community as a gathering of politicallymotivated authority figures who wish to limit our freedoms for socially valid reasons. There is noquestion but that the pendulum is swinging more and more to the side of restrictions and punishment,but any voice that speaks too loudly against this position is condemned as "sending the wrongmessage." In the medical area, this division is extreme. The definition of a Schedule I drug is that it has a high abuse potential and no accepted medical utility. Yet there is no provision for any abusepotential other than "high" nor any statutory guidance as to what would constitute "accepted."There is the voice of the "drug warrior" camp that there can be no toleration of any use of ascheduled drug until it has been proven to be safe. There is the counter voice of the "legalizers" thatthere is no research permitted to establish hazard and, furthermore, there is no definition of thenature of the needed evidence that would constitute proof of safety.
The extremes of this positional separation are just as dramatic in the area of scientific research.
In the academic world there has been a gradual shifting of research funding sources from the interestsof the University to the interests of the Government. Today a very large percentage of research atboth the graduate and the post-doctoral levels is supported by grants from any of several institutes inWashington. And, as the recipients of these grants are increasingly beholden to the political bodiesthat fund them, they effectively define what is acceptable science. Whereas grant applications wereoriginally chosen to reflect the questions arising out of the curiosity of the experimenter, now theyusually reflect the quest for answers that would be of interest to the funder. And again, in the area ofdrugs this is strongly biased towards the perceived need for information that would support the war ondrugs and further justify its escalation. Many grants are awarded specifically to document somenegative property of a given drug, rather than simply to search for the properties of that drug.
I would like to propose a middle ground within this turmoil. The perceived "drug" crisis is thought by most people to reflect the use of stimulants and narcotics, with a generous sprinkling ofmarijuana. There are obvious problems with the stimulants, cocaine and methamphetamine, as wellas with the depressants opium and heroin. And marijuana is the favorite bête noire as it is the defacto major justification for our entire law enforcement's existence. Without this plant, our need ofdrug law enforcement would collapse to about one fifth of where it is today. But, almost unnoticedare the psychedelic drugs which are quite different and distinct. They have been caught up in thisanti-drug rubric, even though very few problems have been specifically associated with this minor category. A few of them, such as LSD and MDMA, have become front-page stuff, and occasionallythere are scare stories in the papers concerning novelties such as toad-licking and mushrooms. But toa large measure, this psychedelic fringe is neither newsworthy nor threatening, within the publicawareness. It rests there largely as an unknown.
Perhaps we can use this relative anonymity as a modest platform, as a foundation, for the development of a research philosophy that is, truly, on middle ground. The political community,along with the law enforcement and the fundamentalist communities, have all found positions at theextremes, and they cannot take a position that even recognizes a middle ground. When a statementis made by a person in power demanding agreement and compliance concerning some evil drugmatter, almost all public figures accept and support his statement. In private, there might be somereservations, but in public there are none. The political position has been lost. But maybe thescientific position has not yet been committed.
Might this community begin to ask questions about a drug such as, "What is its action?" rather than, "Does it have a good or a bad action?" "What is the mechanism of action?" rather than,"What is the mechanism of neurotoxicity?" Small changes such as these would in no way change theintended research protocols, and what is to be observed will still be observed.
Many scientists in the academic community are to some degree intimidated by subtle restraints, and are thus unable to talk with complete candor. But I believe that it is in this very community thatthe battle-lines of the war on drugs have not yet been cast in stone, and that honest inquiry mightstill be sought.
Here is a request to the scientists of the world. The next time you submit a grant proposal, state your questions as being from your curiosity, rather than from a search for answers that might bringyou government approval. Think twice about framing your question as an answer that you expect toverify experimentally. The excitement of science is in discovery, not in confirmation.
As research scientists, we still command a broad audience, and we do not need to become political lackeys. We must remain articulate. We must remain sincere. And we must retain our integrity.
We are the middle ground in a very polarized system, and we must confirm and expand that centralposition.
Alexander Shulgin Lafayette, California On November 23, 1897, Dr. Arthur Heffter, an outstanding German scientist with training in chemistry, pharmacology, and medicine, performed a careful self experiment with one of thealkaloids that he had isolated from a small cactus. On the 100th anniversary of that date, it seems anauspicious time to be introducing what we hope will be the first of a series of Reviews, named inhonor of Dr. Heffter.
The results he obtained on that day established for the first time that a specific chemical substance, which he named mescaline, was responsible for the dramatic and profound psychopharma-cological effects that followed the ingestion of a small Southwestern American cactus that had beennamed peyotl by the Aztec Indians. This cactus, now known as peyote (Lophophora williamsii) wasthe subject of intense intellectual curiosity in the early part of the 20th century. It presently servesas the sacrament for the Native American Church but has been utilized for millenia as the focus ofreligious rituals by indigenous Indian peoples in the Americas.
In 1943, Dr. Albert Hofmann, a research chemist working at the Sandoz laboratories in Basle, Switzerland, accidentally discovered that a substance he had synthesized in 1938, named LSD-25, hadsimilar profound effects on the psyche. Thus began a relatively short-lived saga that led Dr.
Hofmann to isolate and identify a number of active principles from "magical" substances that hadbeen used since antiquity by preindustrial cultures. While mescaline is a simple phenethylamine,perhaps more closely related in structure to the neurotransmitter known as dopamine, it proved to bethe case that LSD, certain active principles in the seeds of morning glories and related plants, invarious psilocybe mushrooms, and in numerous snuffs and plant decoctions used by South AmericanIndians were all built around a chemical scaffold known as tryptamine, the same template upon whichthe ancient and natural brain neurotransmitter known as serotonin is constructed. The discovery ofLSD, and the recognition of this chemical relationship, helped to catalyze the revolution inneuroscience that continues today, and led to early awareness of the importance of the role ofserotonin in the brain.
While there was a period during the 1950s where artists and philosophers explored the magical properties of these newly rediscovered but ancient materials, ultimately their profound andineffable effects on the human psyche have led to widespread use by generations of adolescents. Ofcourse, no one reading this material will be unfamiliar with the fact that these substances, knownvariously as psychedelics or hallucinogens, are now classified in a restrictive drug category that seemsto hold the attention of only a handful of research scientists throughout the world. It has been theaim of the Heffter Research Institute (http://www.heffter.org) to foster and maintain research interestin these substances, until the day that their value as research tools and potential therapeutic agentsmay again be recognized.
There has been no generally recognized forum for the discussion of psychedelic agents by scientists for many years. Many current sources are anonymously authored, and contain anecdotes,the equivalent of old wife's tales, or urban myths, serving only to propagate and createmisinformation, something the Heffter Institute adamantly opposes. It is the aim of the Institute,with this inaugural volume, to begin the periodic publication of a series of reviews that will place intoperspective current research with psychedelic agents. It is hoped that in these pages, and in futurevolumes of the Review, a dialogue can be maintained that will convey to readers a real impression ofthe state of the art in this exciting research arena. Theoretical, practical, and clinical issues will beaddressed and as time passes we hope that the number and scope of the contributions to the reviewwill increase.
West Lafayette, Indiana San Diego, California 1. Antiquity of the Use of New World Hallucinogens
Richard Evans Schultes, Ph.D., F.M.L.S "In the exudates and decoctions from trees and herbs, man has found principles that have permitted him to experience a kinship with the whole of creation." -- William Emboden (1979) A review of psychoactive plants known from archaeological contexts and artistic representations shows that their use has spanned centuries, continuing in places in Mexico and South America to the present day. Thediscovery of the unusual properties of these plants took place as part of the exploration of the physical milieu of theWestern Hemisphere. That these plants must in some cases be made into infusions in order to be consumed revealsancient enterprise in manipulating aspects of the environment. The surprising results obtained from treatingpsychoactive plants allowed their users to communicate more directly with the unseen world which they believed toexist.
It was the great German toxicologist Louis Lewin (1931) who wrote that "from the beginning of our knowledge of man, we find him consuming substances of no nutritive value, but taken for the sole purpose ofproducing for a certain time a feeling of contentment, ease and comfort." There is ample material proof that narcotics and other psychoactive plants, such as hallucinogens, were employed in many cultures in both hemispheres thousands of years ago. The material proof exists in somearchaeological specimens of the plants in contexts indicating magico-religious use and in art forms such aspaintings, rock carvings, golden amulets, ceramic artifacts, stone figurines, and monuments.
Aquifoliaceae Guayusa (Ilex Guayusa)
the grave with great care, gave positive tests for Guayusa, while probably not hallucinogenic as caffeine after 1500 years (Schultes 1972).
ordinarily used, is definitely psychoactive, due to its Several caffeine-yielding species of Ilex have high concentration of caffeine. A tea of the leaves is been the source of beverages, especially yerba maté still used by the Jivaro and other Indians in Ecuador in Argentina, yaupon in the southeastern United as a stimulant and, in highly concentrated doses, as States, shui-chatze in Tibet and China (Hartwich an emetic for purification before ceremonies or 1911; Hu 1979). The presence in the Bolivian burial important tribal conferences. These functions were of so much equipment associated with snuffing and well developed long before the Spanish Conquest, the actual remnants of a powder clearly indicate that and the Jesuits early established a lucrative market the leaves were taken as a snuff: there is no reason to for the leaves in Europe as a cure for syphilis and believe that caffeine administered in this way would other diseases; according to their records, they not be absorbed into the general circulation through maintained a large plantation of Ilex Guayusa in the nasal mucosa. This discovery is the only one southern Colombia, the remnants of which can still which unequivocally shows that a caffeine-rich be seen (Patiño 1968; Schultes 1979). Today, product was used as a snuff.
guayusa leaves are sold for medicinal purposes in If the extra tubes are correctly interpreted as Quito, Ecuador, and Pasto, Colombia, where they clysters, they may further indicate application by were believed to cure a wide spectrum of ills.
enema, in which caffeine could likewise be absorbed It was with great surprise that an archaeological into the general circulation. No caffeine-rich plant find indicated the early use of these leaves in distant has ever been known to have been used in this way, Bolivia. In the tomb of a medicine man of the although rectal administration of tobacco, yopo, and culture, dated about A.D. 500, were found several other drugs in the New World is clearly perfectly preserved bundles of flattened leaves neatly tied with fibrous material. In association with thesebundles was a snuffing tube, other tubes that have Yaupon (Ilex vomitoria)
been interpreted as clysters, bamboo storage tubes for In the southeastern part of the United States, the powder, spatulas, snuff trays, and a mortar and Indians were employing a strong tea of Ilex pestle. The guayusa leaves, which were prepared for vomitoria - known as the Black Drink - as a Schultes, Antiquity of Hallucinogen Use ceremonial stimulant and emetic when the first now known that mushroom ceremonies in southern Europeans arrived (Hale 1891; Milanich 1979).
Mexico use at least two dozen species of mushrooms This tea was made by boiling large doses of leaves in several genera, the most important being for a long time, until the resulting solution was a Stropharia, Psilocybe, and Panaeolus (Guzmán 1959; dark green. In such concentrated infusions, the plant 1977; Heim 1963; Ott and Bigwood 1978; Schultes easily acts as an emetic and, so far as we know from 1939; 1969; Singer 1958; Wasson 1973; Wasson and early records, this ritualistic cleansing of the body Wasson 1957).
before important tribal convocations was its The mushrooms are usually employed fresh and principal use amongst the American Indians - a dry. Their shamanistic use is today extraordinarily custom closely paralleled by the use of guayusa today important, especially among the Indians of Oaxaca.
among the Jivaros of Ecuador.
The officiating shaman in tribes of southern Mexico Evidence of its use in North America from - Mazatecs, Zapotecs, and others - may often be a archaeological contexts is circumstantial but woman. The all-night ceremony among the convincing. Cult objects from gravesites such as Mazatecs of the Sierra Juarez of Oaxaca often shell drinking cups engraved with cult symbols have includes a curing ritual; the most famous of the been interpreted as vessels for the ceremony of the shamans of this region, Maria Sabina, sings Black Drink. These shell cups, dating ca. A.D.
throughout the night and prays for power from 1200, were widespread in the Southeast. Residues spiritual realms through the mushrooms. Since the believed to be from evaporated Black Drink have modern ceremony is part-Christian, part pagan, all been found in some (Milanich 1979).
possible help is implored. The following samplingof the night-long chants in Mazatec (translated) shows their variety: Teonanacatl (Stropharia cubensis; Panaeolus The law which is goodLawyer woman am I. The early Spanish ecclesiastics in conquered Woman of paper work am I. Mexico were much disturbed by pagan religions I go to the sky, centered upon the sacramental use of several Woman who stops the world am I. mushrooms known in Nahuatl as teonanacatl ("flesh Legendary woman who cures am I. of the gods"). Divination, prophecy, communion Father Jesus Christ with the spirit world, and curing rituals depended I am truly a woman of law, upon the narcotic intoxication induced by these I am truly a woman of justice. mushrooms and interpretation of the visual and/or Woman of space am I, auditory hallucinations accompanying the intoxi- Woman of day am I, cation. Persecution drove these Indian practices into Woman of light am I. the hinterland, so no archaeological evidence of the I give account to my Lord magico-religious use of mushrooms was found for a And I give account to the judge, long time. It was even doubted that teonanacatl was And I give account to the government, a mushroom; the idea that, because a dried And I give account to the Father Jesus Christ, mushroom resembled the dried top of the peyote And my mother princess, my patron mother. cactus, teonanacatl was but another name for peyote Oh, Jesus, Father Jesus Christ, was widely accepted (Safford 1915). Not until the Woman of danger am I, late 1930s and early 1940s were identifiable Woman of beauty am I. mushrooms collected from contexts interpreted asceremonial (Schultes 1939). The modern center of The antiquity of sacred mushroom cults in the area in which this mushroom is used is in the Mexico and adjacent areas is now well established, Mexican state of Oaxaca, among the Mazatecs.
and they appear to have deep roots in centuries of The velada or mushroom ceremony among the native tradition. Frescoes from central Mexico dated Mazatecs is usually held in response to a request by a to AD 300, indicate that mushroom worship goes person needing to consult the mushrooms about a back at least 1700 years (Wasson 1980). Stylized problem. A complicated diagnostic or curing ritual mushroom caps - undoubtedly Psilocybe aztecorum - frequently takes place during an all-night ceremony decorate the pedestal of a statue of Xochipili (Aztec (Schultes 1939; Wasson et al. 1974). One or two god of flowers) discovered on the slopes of Mount monitors who do not take the mushrooms must be Popocatepetl and dated to approximately AD 1450 present to listen to what is said. Certain abstinences (Wasson 1973). A terra-cotta artifact, ca. 100-300 must be practiced preparatory to the ceremony. It is AD, found in Colimo, shows figures dancing around The Heffter Review of Psychedelic Research, Volume 1, 1998 a Psilocybe-like mushroom (Furst 1974). Clay williamsii), today widely valued as a sacred figurines with mushroom effigy "horns" from Jalisco intoxicant in magico-religious ceremonies in central are about 1800 years old (Furst 1974). A terra-cotta and northern Mexico and the basis of a religious cult figurine of the Remojadas style found in Vera Cruz among Indians of the United States and Canada - depicts a curandera praying over a mushroom; the was of great age. It is the spineless top of the peyote artifact is about 2000 years old (Heim 1967).
cactus that is usually taken in Indian ceremonies.
Even more remarkable are the so-called Most frequently, it is dried into a so-called "peyote "mushroom stones" found at highland Mayan sites in button," but sometimes the freshly severed crown of Guatemala. These are dated at about 500 BC or the plant may be used (Schultes 1938). The Huichol earlier. Each consists of on upright stipe with a Indians of Mexico, for example, make an annual human or animal figure, the whole crowned with an sacred pilgrimage to Wiricuta - home of the peyote umbrella-shaped top. Long puzzling to plant - to collect with complex ceremonies enough archeologists, they were once interpreted as phallic crowns of the cactus for use during the coming year symbols. Now it is quite widely accepted that they (Furst 1972; Meyerhoff 1974). In the United States, were associated with a mushroom cult, perhaps, as in regions far removed from areas in which peyote has been suggested, with a Meso-American ball exists, the members of the peyote cult, organized into game ritual, itself a religious ceremony. These the Native American Church, may receive their artifacts appear to indicate a very early sophisticated supplies of peyote quite legally in the form of dried mushroom cult far beyond the present Mexican peyote buttons (Schultes 1937). These "buttons" are geographical limits of the magico-religious use of consumed ceremonially with no preparation. Held in the fungi (Borhegyi 1961; Furst 1974; Mayer 1977; the mouth until thoroughly moistened, they are then Ott and Bigwood 1978).
swallowed; a native worshipper in the all-night There is today no evidence that hallucinogenic peyote ceremony in the United States may consume mushrooms are ceremonially employed by Indian up to 25 or 30 buttons in one night (La Barre 1964).
groups in South America. It is possible, however, There is now firm evidence of the great that they were so used in northern Colombia at a antiquity of the reverence of this cactus as a divine or period from 100 to 350 AD. In the Gold Museum in sacred plant. The earliest European reports of peyote Bogota, there are many anthropomorphic pectorals intimate that the Chicimecos and Toltecs of Mexico from the Sinú Culture (Schultes and Bright 1979).
were acquainted with it as early as 300 BC, although The earlier, more realistic of these gold artifacts the accuracy of the dating depends on the have hemispherical caps separated from the head by interpretation of native calendars (Anderson 1980; definite stipes; in later models, both the human Schultes 1938); thus the date may even be earlier.
figure and the dome shaped cap become stylized - Recent archeological finds in shelters and caves the domes losing their stipe and becoming affixed in the Cuatro Cienegas Basin in Coahuila, Mexico, directly to the idol. These spherical domes have led and trans-Pecos, Texas, dated by 14C and spanning to their identification as pectorals for lack of a better some 8000 years of intermittent human occupation, explanation of their use, "telephone bell gods", included, among other plant remains, identifiable because of the two domes on the heads that specimens of Lophophora williamsii - often in suggested old fashioned telephones. Significant is abundance and in a context that suggests ritual use.
the presence on many of these pectorals of a toad or The peyote was accompanied by quantities of seeds frog, animals of great magico-religious importance of the hallucinogenic red bean (Sophora in connection with intoxication in ancient and secundiflora) and the toxic Mexican buckeye modern Andean cultures. The discovery in the (Ungnadia speciosa) which is suspected to be region of the Sinú Culture of a number of species of psychotropic (Adovasio and Fry 1976).
Psilocybe, some of which are provided with the Of great significance are ceramic bowls from hallucinogenic constituent psilocybin, strengthens Colima, Mexico, dated about 100 BC to 200-300 the suggestion that these pectorals may indicate the AD, with four peyote like ornaments and a male ceremonial use of psychoactive mushrooms in hunchbacked figure (also from Colima and of the magico-religious rituals among the Indians of same age) holding a pair of peyote plants (Furst northern Colombia (Schultes and Bright 1979).
1974). It has been suggested that the plants in theColima peyote effigy may indicate incipient or temporary domestication of the cactus in prehistoric Peyote (Lophophora williamsii) - It has long been suspected that the use of the Mexicanhallucinogenic cactus peyote (Lophophora Schultes, Antiquity of Hallucinogen Use San Pedro Cactus (Trichocereus pachanoi)
alkaloid that is responsible for the visions induced by There exists today a folk-healing ceremony the peyote cactus (Schultes 1980).
based in part on the use of the hallucinogenic cactusknown in Andean South America as San Pedro, San Pedrillo, aguacolla, and gigantón. A brew of the Ololiuqui (Turbina corymbosa, Ipomoea stems of this tall cactus is prepared, often with other psychoactive plants added (e.g., the Solanaceous A number of Spanish chroniclers of the time of Brugmansia candida or floripondio). The brew is the Conquest of Mexico described in detail the employed in magic ceremonies, as a medicine and to religious and medicinal use of a small lentil-like protect homes, "as if it were a dog." A drink seed known to the Aztecs as ololiuqui. Its source prepared of the soft interior of the stems of the cactus was a vine called coatlxoxouhqui, which was clearly is also administered in ceremonial contexts. In the a morning glory (Reko 1934; Schultes 1941). For highland Indian markets of Peru and Bolivia, cut nearly four centuries, no species of the Morning pieces of the stem of the cactus are sold for Glory Family was found in use as a divinatory preparation of the sacred, intoxicating drink. The hallucinogen, and no psychoactive principle was San Pedro cactus is now widely employed in Peru known until recently in the family Convolvulaceae.
and Bolivia in curing ceremonies that combine Many .writers accepted the suggestion that ololiuqui Christian and pre-Columbian native elements (Davis was a member of the toxic Nightshade Family (a 1983; Sharon 1972; 1978). The use of this cactus species of Datura), although there were voices of goes far back in prehistory, and there is evidence protest (Reko 1934). It was not until the 1930s that that its ritual utilization was widespread in the identifiable material associated with its magico- central Andes at the time of the Spanish Conquest.
religious use as collected in Oaxaca (Schultes 1941).
There exist two references to this "plant with which The source plant encountered "in almost all the the devil deceived the Indians" from European villages of Oaxaca (where) one finds seeds still ecclesiastical reports of the mid-fifteenth century serving the natives as an ever present help in time of (Sharon 1972).
trouble" (Wasson 1963).
There are, in addition, artifacts that indicate that The use of these morning glory seeds as sacred its use in Peru goes back at least three thousand intoxicants in curative ceremonies of ancient origin years. The oldest known evidence of this kind is a seems to be focused in Oaxaca, Mexico. In the stone excavated at Chavín de Huantar in the Mazatec country of that state, the seeds must be northern Peruvian Andes; dating from about 1300 ground on a metate (quern) by a maiden and BC, it is carved with a mythological being holding a prepared in a cold-water solution. The resulting section of stem of the cactus. Chavín textiles from drink is given to the patient, and the mumblings that the south coastal region of Peru show the cactus in he makes during his intoxication are interpreted by association with the jaguar, an animal associated on assistant whose task is to listen.
throughout Andean South America with intoxication Two species of morning glories are employed in and hallucinogens; these textiles are dated in the Oaxaca: Turbina corymbosa with small, round, first millennium BC (Sharon 1972). Ceramics dating brown seeds, and Ipomoea violacea with larger, from 500 to 1000 AD depict sections of the San angular, jet black seeds. The chemical constituents Pedro cactus together with the jaguar (Furst 1972).
in the two species differ. The total ergoline alkaloid The use of this hallucinogen apparently continued on content of the seeds of the former species is 0.012 the southern coast of Peru after the decline of the percent, whereas of the latter it is 0.06 percent. This Chavín influence; four ceramic urns in the form of fact explains why Indians use smaller quantities of mummy bundles from the Nasca culture, dated from seeds of I. violacea than of T. corymbosa (Schultes 100 BC to AD 500 have been found with representations of the stem of the cactus protruding Ololiuqui was one of the most important from each shoulder (Sharon 1972). In northern hallucinogens in ancient Mexico. The plant is Peru, ceramic vessels with representations of San depicted in mural painting at Teotihuacan and Pedro date to about 400 to 200 BC. (Sharon 1972).
Tepantitla. These murals show the water goddess At the present time, the ritual is extensively with a stylized vine of the sacred hallucinogenic practiced by shamans in the coastal regions of Peru, morning glory (Furst 1974).
where it has heavy Christian overtones (Sharon We know much about the pre-Conquest use of 1972). Trichocereus pachanoi has as its active ololiuqui because of the numerous detailed reports hallucinogenic constituent mescaline, the same made immediately after the arrival of the Spaniards.
The personal physician of the king of Spain, Dr.
The Heffter Review of Psychedelic Research, Volume 1, 1998 Francisco Hernández, wrote of the medicinal and true of yopo, a hallucinogenic snuff prepared from magico-religious use of ololiuqui among the Aztecs the beans of a leguminous tree - Anadenanthera between 1570 and 1575, a five-year period during peregrina, formerly known by the binomial which he was studying the native medicinal plants of Piptadenia peregrina (Altschul 1964). This Mexico; he figured the source plant was a morning psychoactive powder was widely used in much of the glory (Schultes 1941). A painting in the Florentine Caribbean (where it was known as cohoba) at the Codex definitely illustrates a morning glory which time of the Spanish Conquest (Safford 1916) but it the Spanish ecclesiastical authorities considered a persists now only in the Orinoco of Colombia and gift of the devil (ibid.).
Venezuela and adjacent parts of Brazil (Altschul1972; Safford 1916). Archaeological remains of snuffing tubes and trays can definitely be associated Red Bean or Mescal Bean (Sophora with the use of this hallucinogen (Torres et al. 1991).
The first scientific report of yopo was given by theexplorer Baron von Humboldt, who witnessed the The red seeds of Sophora secundiflora, a preparation of the snuff on the Rio Orinoco in 1801 beautiful shrub of the dry parts of northern Mexico (Schultes and Hofmann 1980). The British botanist and the southwestern United States, once formed the Spruce in 1851 offered an extremely detailed basis of a vision-seeking ceremony practiced by a description of the preparation and use of the drug number of Indian tribes (Adovasio and Fry 1976; (ibid.). The glossy black beans -five to twenty in Schultes 1969; Schultes and Hofmann 1979). The each pod - are toasted and pulverized. The powder ceremony was known variously as the Red Bean is then sifted and mixed in equal parts with the Dance, the Wichita Dance, or the Deer Dance alkaline ashes of certain barks or leaves, especially (Campbell 1958). The ingestion of the red beans is ashes of the bark of a wild member of Theobroma, extremely dangerous, since the active alkaloid - the genus that yields cacao or chocolate (ibid.).
cytisine - is highly toxic and can cause death by A missionary in the Colombian Orinoco wrote asphyxiation, by attacking the phrenic nerve in 1560 that the Indians living along the Rio controlling movement of the diaphragm. As the Guaviare "are accustomed to take yopo and tobacco, ritual employment of the safe peyote cactus spread and the former is a seed or pip of a tree . . they northward from Mexico, the use of the red bean become drowsy while the devil, in their dreams, gradually died out, although it is believed that shows them all the vanities and corruptions he occasionally both hallucinogens were taken together wishes them to see and which they take to be true in the early days of peyote use in the United States.
revelations in which they believe, even if told they It is true, however, that today in certain American will die" (Schultes and Hofmann 1979). Yopo was tribes part of the ritual dress of the leader of the so important in pre-Conquest Colombia that Indians peyote ceremony consists of a necklace of this once of the highlands, where the tree will not grow, sacred narcotic seed - the only vestige of the former acquired the drug in trade from the tropical role of this toxic hallucinogen. Cabeza de Vaca, one of the early Spanish explorers of Texas, reported in Yopo snuff is often token daily as a stimulant, 1539 that these seeds were an article of trade among but it is more commonly employed by payés the Indians of the region (Schultes 1980). Now, ("medicine men") to induce trances and visions and however, there is archaeological evidence for the use communicate with the hekula spirits; to prophesy or of Sophora secundiflore (Adovasio and Fry 1976).
divine; to protect the tribe against epidemics of Caches of the red bean have been discovered in sickness; to make hunters and even their dogs more numerous archaeological sites in northeastern alert. Yopo is quick acting. It first causes a profuse Mexico and trans-Pecos Mexico, often in association flow of mucous from the nasal passages and with peyote and Mexican buckeye seeds. These sites, occasionally a noticeable quivering of the muscles, dated by 14C, span the period from 7000 BC to AD particularly of the arms, and a contorted expression 1000. The vegetal materials often provided evidence of the face. This period soon gives way to one in of potential ceremonial use, possibly in a hunting which the shamans begin to prance, gesticulating cult (Adovasio and Fry 1976).
and shrieking violently. This expenditure of energyto frighten away the hekula spirits lasts up to an Yopo and Vilca
hour. Eventually fully spent, the shamans fall into a (Anadenanthera peregrina and A. colubrina) trance-like stupor, during which nightmarishhallucinations are experienced.
It is not usual that archaeological remains of In the more southerly parts of South America, plants are found in the wet tropics, although this is the Indians prepared a snuff from another species of Schultes, Antiquity of Hallucinogen Use Anadenanthera: A. colubrina (Califano 1976). It is Campbell, T. N. (1958) Origin of the Mescal Bean still employed by Indians in northern Argentina, Cult. American Anthropologist 60: 156-160.
where it is known as huilca or vilca and cebil Davis E. W (1983) Sacred Plants of the San Pedro (Altschul 1967). There is evidence from native art Cult. Botanical Museum Leaflets (Harvard that vilca was a plant associated in Peru with University) 29: 367-386 Furst, P. T. (1972) To Find Our Life: Peyote among the Huichol Indians of Mexico. In: Furst, P.T.
(Ed.) Flesh of the Gods. New York, Praeger, pp.
The discovery of plants with psychoactivity must be attributed to millennia of trial and error Furst, P. T. (1974) Hallucinogens in Precolumbian experimentation with most or all of the plants in the Art. In: King, E.M. and Traylor (Ed.) Art and ambient vegetation of native peoples. There can be Environment in Native America. Texas no other explanation. When the unearthly and Technical University, Special Publications of the inexplicably weird physical and psychic effects of Museum, no. 7, pp. 55-102.
these few plants were experienced, it did not take Guzmán, H. G. (1959) Sinopsis de los conocimientos long for primitive societies to regard them as sacred sobre los hongos aluciogenos mexicanos. Boletin elements of the flora, and their use eventually fell Sociedad Botánico de Mexico 24: 14-34.
into the province of the shamans or medicine men Guzmán, H. G. (1977) Identificación de los Hongos who explained their effects as proof that these Comestibles y Alucinantes. Mexico City, species were the home of spirits or spiritual forces Editorial Limusa.
enabling man through various hallucinations to Hale, E. M. (1891) Ilex cassine, the Aboriginal communicate with ancestors or with spirits in the North American Tea. U.S.D.A Division of outer realms.
Botany Bulletin 14: 7-22., Washington, D.C., Thus, most of these powerful members of the Govt. Printing Office vegetal kingdom became the central figures in Hartwich, C. (1911) Die menschlichen Genusmittel.
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persisted in many regions to the present time. The Heim, R. (1963) les Champignons toxiques et role of the plants, as archaeological artifacts and hallucinogénes. Paris, N. Boubée et Cie.
other ancient records attest, has changed little with Hu, Shiu-Ying (1979) The Botany of Yaupon. In: the passage of time. They remain, in effect, what Hudson, C.M. (Ed.) Black Drink - A Native has been called "plants of the gods." American Tea. Athens, University of GeorgiaPress, pp. 10-39.
la Barre, W. (1938) The Peyote Cult. Yale University Publications in Anthropology, no. 19. New Adovasio, J. M. and G. F. Fry (1976) Prehistoric Haven, Yale University Press; rev. ed., Shoe Psychotropic Drug Use in Northeastern Mexico String Press, Inc., Hamden, Connecticut (1964).
and Trans-Pecos Texas. Economic Botany 30: Lewin, L. (1931) Phantastica: Narcotic and Stimulating Drugs. London, Kegan Paul, Altschul, S. von R. (1964) A Taxonomic Study of Trench, Trubner & Co., Ltd.
the Genus Anadenanthera. Contrib. Gray Herb.
Moyer, K. H. (1977) The Mushroom Stones of Mesoamerica. Ramona, California, Acoma Schultes, R. E., Vilca and its Use. (1967) In: Efron, D.H. (Ed.) Ethnopharmacologic Search for Meyerhoff, B. G. (1974) Peyote Hunt. The Sacred Psychoactive Drugs. Washington, D.C., US.
Journey of the Huichol Indians. Ithaca, Cornell Public Health Service Publ. no. 1645, pp. 307- University Press.
Milanich, J. T. (1979) Origins and Prehistoric Schultes, R. E., The Genus Anadenanthera in Distributions of Black Drink and the Amerindian Cultures. (1972) Cambridge, Mass., Ceremoniol Shell Drinking Cup. In: Hudson, Botanical Museum, Harvard University.
C.M. (Ed.) Black Drink - A Native American Anderson, E. F. (1980) Peyote - the Divine Cactus.
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Borhegyi, S. A. (1961) Miniature Mushroom Stones Ott, J. and J. Bigwood, (Eds.) (1978) Teonanacatl.
from Guatemala. American Antiquity 26: 498- Hallucinogenic Mushrooms of North America, part I: 5-113. Seattle, Washington, Madrona Califano, M. (1976) El Chamanismo Mataco.
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and Chemistry of Hallucinogens. 2nd ed., Economic Botany 22: 310-316.
Springfield, Illinois, Charles C. Thomas.
Reko, B. P. (1934) Das mexikanische Rauschgift Sharon, D. (1972) The San Pedro Cactus in Ololiuqui. El Mexico Antiguo 3, nos. 3-4: 1-7.
Peruvian Folk Healing. In: Furst P.T. (Ed.) Safford, W. E. (1915) An Aztec Narcotic. Journal Flesh of the Gods: the Ritual Use of of Heredity 6: 291-311.
Hallucinogens. New York, Praeger, pp. 114- Safford, W. E. (1916) ldentity of Cohoba. Journal of the Washington Academy of Sciences 6: 547- Singer, H. (1958) Mycological Investigations on Teonanacatl, the Mexican Hallucinogenic Schultes, R. E. (1937) Peyote (Lophophora Mushroom. Part 1. The History of Teonanacatl, williamsi) and Plants Confused with It.
Field Work and Culture Work. Mycologia 50: Botanical Museum Leaflets (Harvard University) Torres, Constantino M.; Repke, D.; Chan, K.; Schultes, R. E. (1938) Peyote - an American Indian McKenna, D.; Llagostera, A. and Schultes, R.
Heritage from Mexico. El Mexico Antiguo 4, E. (1991) Snuff powders from Pre-Hispanic San nos. 4-6: 199-208.
Pedro de Atacama: Chemical and contextual Schultes, R. E. (1939) Plantae Mexicanae II. The analysis. Current Anthropology, vol. 32, no. 5: Identification of Teonanacatl, a Narcotic Basidiomycete of the Aztecs. Botanical MuseumLeaflets (Harvard University) 7: 37-54.
Wasson, R. G. (1980) The Wondrous Mushroom: Schultes, R. E. (1941) . A Contribution to our Mycolatry in Mesoamerica. New York, McGraw Knowledge of Rivea corymbosa, the Narcotic Hill Book Co.
Ololiuqui of the Aztecs. Cambridge, Mass., Wasson, R.G. (1963) Notes on the Present Status of Harvard Botanical Museum.
Ololiuqui and the other Hallucinogens of Schultes, R. E. (1969) Hallucinogens of Plant Mexico. Botanical Museum Leaflets (Harvard Origin. Science 163: 245-254.
University) 20: 161-193.
Schultes, R. E. (1972) Ilex Guayusa from 500 AD to Wasson, R.G. (1972) The Divine Mushroom of the Present. Etnologiska Studier 32: 115-138.
Immortality. In: Furst, P.T. (Ed.) Flesh of the Schultes, R. E. (1979) Discovery of an Ancient Gods - the Ritual Use of Hallucinogens. New Guayusa Plantation in Colombia. Botanical York, Praeger, pp. 185-200.
Museum Leaflets (Harvard University) 27: 143- Wasson, R.G. (1973) The Role of 'Flowers' in Nahuatl Culture, a Suggested Interpretation.
Schultes, R. E. and A. Bright (1979) Ancient Gold Botanical Museum Leaflet (Harvard University) Pectorals from Colombia: Mushroom Effigies? 23: 305-324.
Botanical Museum Leaflets (Harvard University) Wasson, R. G., G. and F. Cowan, and W. Rhodes.
27:113-141. Reprinted in Sweat of the Sun, (1974) Maria Sabina and the Mushroom Velada.
Tears of the Moon: Gold and Emerald Treasures New York, Harcourt Brace Jovanovich.
of Colombia. Natural History Museum of Los Wasson, V. P. and R.G. Wasson (1957) Angeles County, Los Angeles: 37-43 (1981) Mushrooms, Russia and History. New York, Schultes, R. E. and A. Hofmann (1979) Plants of the Gods - Origins of Hallucinogenic Use. NewYork, McGraw-Hill Book Co.
This article was adapted from an earlier publication that appeared in "Integration 5", in Autumn 1994. 2. Psychiatric Research with Hallucinogens: What have we learned?
Charles S. Grob, M.D.
Psychiatric research with hallucinogens has revelatory access to the sacred (Dobkin de Rios and resumed. After two decades of virtual prohibition, Smith, 1976). In some societies (e.g. Aztec civilization) formal authorization from federal regulatory agencies to use of psychotropic plants was restricted to the select conduct investigative studies in the United States with castes of the religious priesthood. In others, including these unique mind altering substances has been the progenitors of our own contemporary Euro- successfully obtained (Strassman, 1991). The bitter and American culture, absolute proscriptions on the use of acrimonious debate that raged through the 1960s and plant drugs for divine purposes were decreed. 1970s and into the 1980s has largely subsided. Scientificand health policy makers have determined that these Repression of Shamanistic Traditions
drugs, although possessing an inherent abuse potential, To fully understand the enormous resistances to do have a safety profile of acceptable magnitude when these drugs and the unique experiences they induce, it compared to drugs currently the subject of formal would be revealing to examine some elements of our research investigation as well as others actively historical legacy. A poorly appreciated period from dispensed in clinical practice. The U.S. Food and Drug Fourteenth through Seventeenth Century European Administration has therefore determined that formal History has been the persecution of indigenous healers, and well controlled investigations designed to assess the predominantly woman, during the reign of the risk-benefit ratio of particular hallucinogenic substances Inquisition, particularly in Northern and Western may now be pursued. However, for such studies to Europe. During a span of three hundred years several proceed successfully and for the much heralded (and million women were accused of practicing witchcraft often vilified) potential of the hallucinogens to be and condemned to die. The Medieval scholar Jules explored, it is imperative that we fully grasp the lessons Michelet has explored the complicity between of the past. For, to paraphrase Santayana, if we fail to ecclesiastical and medical authorities in the subjugation understand our history, we will be condemned to repeat of non-sanctioned healing, commenting on the attitude the patterns and reactions which will inevitably lead to of the Church "that if a woman dare cure without yet another round of repudiation and rejection of this having studied, she is a witch and must die" (Michelet, unique class of psychoactive substances, along with its 1965). To have "studied" in this context is to have inherent and inestimable potential for learning and faithfully adhered to the precepts and moral authority of the Church, and to have forsworn receiving knowledgefrom Nature.
A rich heritage of plant lore and applied healing Hallucinogens, throughout the breadth of time, had been passed down from pagan and pre-Christian have played a vital albeit hidden and mysterious role.
Europe, rivaling and often surpassing the demonstrated They have often, in aboriginal and shamanic contexts, efficacy of Church sanctioned medical practitioners.
been at the absolute center of culture and world view Hallucinogenic plants with magical as well as healing (Dobkin de Rios, 1984). Opening up the doors to the properties were essential elements of this indigenous spiritual planes, and accessing vital information pharmacopoeia. Members of the Solanaceae family imperative to tribal cohesion and survival, with their alkaloids atropine and scopolamine, including hallucinogenic plants became what some scholars have a great number of species of the genus Datura, as well as considered to be the bedrock of human civilization mandrake, henbane, and belladonna, had wide (Wasson, 1968; Wasson et al, 1978; Huxley, 1978).
application as agents of healing and transcendence Within the context of shamanic society, these awe (Harner, 1973). In taking action against the indigenous inspiring botanicals were utilized to facilitate healing, use of psychotropic plants, the Church sought to divine the future, protect the community from danger eliminate a perceived threat to its oligarchic powers and and enhance learning (e.g. teaching hunters the ways of reassert its monopoly on legitimate access to the animals) (Cordova-Rios, 1971). However, with the supernatural (O'Neil, 1987). By casting the healer as a advent of stratified and hierarchical societies, such plant witch and the hallucinogenic plants as tools of Satan, potentiators came to be viewed as dangerous to the the Church succeeded not only in eliminating commonweal and controls were placed on direct and competition to the elite physician class but also in Grob, Psychiatric Research with Hallucinogens virtually eradicating knowledge of these vestiges of deeply underground and maintaining their world view pagan and shamanic consciousness.
and shamanic practices in secret from the dominant A second historical period whose examination may Euro-American culture, has this knowledge survived.
be pertinent to understanding our ingrained culturalresistances and aversion to hallucinogens is the Early Research with Hallucinogens
European conquest of the New World. Shortly after Interest in plant hallucinogens lay dormant until arrival in Central and South America in the late the second half of the Nineteenth Century when Fifteenth and early Sixteenth Centuries, the invading growing activities in the new fields of experimental Spanish Conquistadors observed an impressive array of physiology and pharmacology sparked efforts at psychoactive pharmacopoeia, including morning glory laboratory analyses of medicinal plants. In the late seeds (containing the potent hallucinogen, lysergic acid 1880's German toxicologist Louis Lewin, often called amide), peyote, and psilocybin mushrooms. the "father of modern psychopharmacology," received a These extraordinary plants were utilized by the collection of peyote samples from the Parke-Davis native inhabitants to induce an ecstatic intoxication and Pharmaceutical Company. Succeeding at isolating were an integral component of their aboriginal religion several alkaloids from the peyote, Lewin was unable to and ritual. As plant hallucinogens were attributed to identify any of them as the psychoactive component have supernatural powers, they were quickly perceived through animal testing. The investigation was then by the European invaders as weapons of the Devil taken up by Arthur Heffter, who characterized designed to prevent the triumph of Christianity over additional pure alkaloids from the cactus. By ingesting traditional Indian religion (Furst, 1976). An early each of them he was able to identify the crucial one, Seventeenth Century Spanish observer of native which he named mescaline (Heffter, 1897). customs, Hernando Ruiz de Alarcon, wrote of the Along with Lewin's published work, interest in idolatries he observed involving the consumption of the plant hallucinogens was encouraged by increasing morning glory: "Olouihqui is a kind of seed-like lentils dissemination of knowledge of the Native American produced by a type of vine in this land, which when Indian use of peyote, a phenomena of increasing drunk deprive of the senses, because it is very powerful, prevalence as the century drew to a close. Obtaining a and by this means they communicate with the devil, sample of peyote from the South-Western plains, because he talks to them when they are deprived of physician and founder of the American Neurological judgment with the said drink, and deceive them with Association Weir Mitchell, conducted an experiment different hallucinations, and they attribute it to a god using himself as the subject. Although overwhelmed they say is inside the seed" (Guerra, 1971).
with the aesthetic power of the experience, describing Identifying the threat not only to consolidating their that the peyote revealed "a certain sense of the things power and control over the conquered peoples, but also about me as having a more positive existence than the danger of lower caste immigrant Spaniards usual," Mitchell expressed alarm that such a profound developing interest in native rituals and healing experience might not be successfully integrated within practices, The Holy Inquisition of Mexico issued in his contemporary context: "I predict a perilous reign of 1616 a proclamation ordering the persecution and the mescal habit . . The temptation to call again the excommunication of those who, under the influence of enchanting magic of my experience will, I am sure, be "herbs and roots with which they lose and confound too much for some men to resist after they have once set their senses, and the illusions and fantastic foot in this land of fairy colors where there seems so representations they have, judge and proclaim much to charm and so little to excite horror or disgust" afterwards as revelation, or true notice of things to (Mitchell, 1896).
come. ." (Guerra, 1967). To continue to engage in Inspired by reports of Mitchell's self- native practices and utilize their traditional plant experimentation, the prominent English physician hallucinogens as agents of knowledge and healing Havelock Ellis decided to pursue a similar encounter would risk indictment of heresy and witchcraft, and with the plant hallucinogen, which he later reported as inevitably the implementation of the cruelest an experience of unparalleled magnitude, asserting that punishments of the Inquisition, from public flogging to to "once or twice be admitted to the rites of mescal is not being burned alive at the stake. Unable to accept the only an unforgettable delight but an educational indigenous utilization of such psychoactive substances influence of no mean value" (Ellis, 1897). Such as anything other than idolatry and a threat to their unqualified praise of a drug with as yet no proven goals of domination and exploitation, the European medical application, however, provoked harsh censure conquerors denied them legitimacy, endeavoring to from the editors of the British Medical Journal who expunge their traditions and knowledge. Only by going The Heffter Review of Psychedelic Research, Volume 1, 1998 expressed grave concern of peyote's injurious potential his home to rest. He subsequently would write that and reprimanded Ellis for irresponsibly "putting the upon reaching home and lying down with his eyes temptation before the section of the public which is closed he experienced an "extreme activity of the always in search of new sensation" (British Medical imagination . . there surged upon me an uninterrupted Journal, 1898). Such a vituperative response to Ellis' stream of fantastic images of extraordinary plasticity naive efforts at publicizing and perhaps promoting auto- and vividness and accompanied by an intense experimentation with magical plants is an early kaleidoscope like play of colors. After about two hours, harbinger of the conflict that mired and paralyzed the the not unpleasant inebriation, which had been field of hallucinogenic research some seventy years experienced while I was fully conscious, disappeared" (Hofmann, 1983). Interest in the unusual psychogenic effects of peyote Concluding that he had probably accidentally and, following its synthesis in 1919, mescaline, absorbed a small quantity of the compound through his continued through the 1920's. Activities included skin, Hofmann set out three days later, on April 19, further exploration of the unique visions induced by the 1943, to replicate the phenomena by self administering drug by a variety of literary figures and scholars what he considered to be an extremely small and introduced to its exotic phenomena, although when cautious dose, 250 micrograms. Intending to record his William James experienced a severe gastro-intestinal subjective experiences of what he had assumed to be a reaction upon attempting to swallow a segment of very low dose of the peculiar substance, less than an peyote he is alleged to have stated: "Henceforth, I'll take hour later Hofmann began to feel the onset of what was the visions on trust" (Stevens, 1987). A comprehensive to be a powerful and indeed frightening altered state of survey of the effects of mescaline was published by Karl consciousness, and again felt compelled to return to his Beringer, a close associate of Hermann Hesse and Carl home. Hofmann would later report "On the way home, Jung, in his massive tome "Der Meskalinrausch" (The my condition began to assume threatening forms. .
Mescaline Inebriation) in 1927, followed a year later by Everything in my field of vision wavered and was Heinrich Kluver's Mescal: The "Divine" Plant and Its distorted as if seen in a curved mirror. I also had the Psychological Effects, the first attempt at formal sensation of being unable to move from the spot.
classification and analysis of mescaline visions (Kluver, Nevertheless, my assistant later told me that we had 1928). And heralding the next phase of hallucinogen traveled very rapidly. . My surroundings had now research, mescaline was touted by psychiatric transformed themselves in more terrifying ways.
researchers as a putative biochemical model for major Everything in the room spun around, and the familiar mental disturbances, particularly schizophrenia objects and pieces of furniture assumed grotesque, (Guttman and Maclay, 1936; Stockings, 1940).
threatening forms. They were in continuous motion,animated, as if driven by an inner restlessness… Even Dr. Hofmann's Serendipitous Discovery
worse than these demonic transformations of the outer The modern era of hallucinogen research began in world, were the alterations that I perceived in myself, in the laboratory of Dr. Albert Hofmann, a senior research my inner being. Every exertion of my will, every chemist for the Sandoz Pharmaceutical Company in attempt to put an end to the disintegrations of the outer Basel, Switzerland. In mid April, 1943, Hofmann was world and the dissolution of my ego, seemed to be engaged in work to chemically modify alkaloids from wasted effort. A demon had invaded me, had taken the rye ergot fungus, Claviceps purpurea, in an effort to possession of my body, mind and soul." Shortly develop a new analeptic agent (a respiratory stimulant).
thereafter, Hofmann would describe, "the climax of my Acting on a premonition that earlier tests had missed despondent condition had passed. . the horror softened something, he returned to and prepared a fresh batch of and gave way to a feeling of good fortune and gratitude.
a compound he had previously synthesized in 1938, but . now, little by little I could begin to enjoy the which had proved at that time to have what were unprecedented colors and plays of shapes that persisted considered to be uninteresting results in animal testing.
behind my closed eyes. Kaleidoscopic, fantastic images The chemical compound he had decided to return to surged in on me, alternating, variegated, opening and after this five year hiatus was the twenty-fifth in a series then closing themselves in circles and spirals, exploding of lysergic acid amides, and had previously received the in colored fountains. . Exhausted, I then slept, to designation of LSD-25.
awake next morning refreshed, with a clear head, While working with a modest quantity of this though still somewhat tired physically. A sensation of compound for further study, Hofmann complained of well-being and renewed life flowed through me " restlessness and feeling dizzy and decided to return to (Hofmann, 1983). Dr. Hofmann's shocking experienceof madness and transcendence, precipitated by an Grob, Psychiatric Research with Hallucinogens infinitesimally low dose of what would soon be those obtained with schizophrenics" (Rinkel and recognized as the most potent psychoactive substance Denber, 1958)., it became increasingly apparent, known to man, heralded the advent of a new era of however, that although an impressive array of psychiatric research committed to uncovering the psychiatric researchers and theoreticians had elucidated mysteries of the mind and revealing the basis of mental and elaborated upon the startling degree of resemblance between schizophrenia and the hallucinogenicexperience, a growing consensus was emerging that the The Psychotomimetic Model
dissimilarities between the two states essentially Albert Hofmann's discovery of LSD soon led to a obviated the value of the chemical psychosis model period of intense interest and activity designed to (Grinspoon and Bakalar, 1979). Speaking at the First explore its utility as a model of understanding and International Congress of Neuropsychopharmacology in treating psychotic illness. Such a direction was 1959, the legendary Manfred Bleuler enunciated the consistent with earlier investigations equating the central argument in opposition to the psychotomimetic mescaline catalyzed altered state of consciousness with model. He stated that it was the gradual and inexorable the subjective experience of schizophrenic patients progression of a symptom complex that included (Guttman and Maclay, 1936; Stockings, 1940). Tayleur disturbed thought processes, depersonalization and Stockings had described the similarities between the two auditory hallucinations, evolving into a generalized states: "Mescaline intoxication is indeed a true functional incapacitation that was characteristic of 'schizophrenia' if we use the word in its literal sense of schizophrenia. He concluded with the demonstrative ‘split mind,' for the characteristic effect of mescaline is declaration that although the psychotomimetic drugs a molecular fragmentation of the entire personality, may have strengthened our conceptual understanding of exactly similar to that found in schizophrenic patients… organic psychoses, they have "contributed nothing to the Thus the subject of the mescaline psychosis may believe understanding of the pathogenesis of schizophrenia" that he has become transformed into some great (Bleuler, 1959).
personage, such as a god or a legendary character, or abeing from another world. This is a well-known Hallucinogen Research and the Role of the CIA
symptom found in states such as paraphrenia and Following the end of World War II, as relations paranoia" (Stockings, 1940). Noting the enormity of with our former ally the Soviet Union began to perceptual disturbances induced by LSD, coupled with deteriorate and Cold War tensions heightened, a the sensation in some subjects of losing their mind, as program was initiated by the U.S. Central Intelligence had transiently been the case with Dr. Hofmann, Sandoz Agency to develop a speech inducing drug for use in in 1947 began actively marketing LSD to psychiatric interrogations of suspected enemy agents. Such a researchers and practitioners as a tool for understanding search was in part stimulated by knowledge of prior, psychoses. Not only was LSD experimentation in albeit unsuccessful, efforts by Nazi medical researchers normal subjects proposed as a viable model for studying at the Dachau Concentration Camp to utilize mescaline the pathogenesis of psychotic illness, but psychiatrists as an agent of mind control (Marks, 1979). By the early were encouraged to self-administer the drug so as to 1950's the CIA had acquired from Sandoz gain insight into the subjective world of the patient with Pharmaceutical a large quantity of the highly touted serious mental illness (Stevens, 1987). For a young psychotomimetic, LSD, and had begun their own field struggling to gain credibility as a medical science, extensive testing program. Early experiments often this model of chemically controlled psychosis emerged involved the furtive "dosing" of unwitting subjects, as a propitious sign for the future. including employees of the CIA and other intelligence Preoccupation with the hallucinogen induced organizations, soldiers and customers solicited by psychotomimetic model continued through the 1950's.
prostitutes in the service of the CIA. Given the ill- The psychotomimetic position was summarized by one prepared mental set of the victim, the often adverse its leading proponents, Harvard psychiatrist Max setting in which the "experiment" occurred, and the lack Rinkel: "The psychotic phenomena produced were of therapeutic aftercare, it is no surprise that highly predominantly schizophrenia-like symptoms, mani- deleterious outcomes, including suicide, did occur.
fested in disturbances of thought and speech, changes in Although knowledge of this irresponsible and ethically affect and mood, changes in perception, production of suspect association between the CIA and hallucinogenic hallucinations and delusions, depersonalizations and substances remained suppressed for the next twenty changes in behavior. Rorschach tests and concrete- years, knowledge of such activities was ultimately abstract thinking tests showed responses quite similar to obtained through the Freedom of Information Act The Heffter Review of Psychedelic Research, Volume 1, 1998 (Marks, 1979; Lee and Schlain, 1985).
uncovering early childhood memories, and inducing an Through the 1950's, as Cold War fears escalated, affective release, psychiatrists claimed to have achieved the CIA began to developed an affinity for the a breakthrough in reducing the duration and improving psychotomimetic model then in vogue. In order to the outcome of psychotherapeutic treatment (Chandler further their own goals of investigating the mind control and Hartmann, 1960). Problems arose with the potentials of hallucinogenic drugs, the CIA began to psycholytic paradigm, however, as critics noted that the recruit and fund a number of distinguished psychiatric content of regressed material released from the researchers. Included among these was Ewen Cameron, unconscious was extremely sensitive to the psychiatrist's elected President of the American Psychiatric own analytic orientation, in most cases Freudian or Association in 1953 and first President of the World Jungian. Questions arose over whether the phenomena Psychiatric Association. Capitalizing on the CIA's observed in the psychotherapeutic sessions, including preoccupation with LSD's purported ability to break the often positive treatment outcome, were not simply down familiar behavior patterns, Cameron received attributable to the presence of heightened powers of funding to develop a bizarre and unorthodox method for suggestibility. Moreover, with psycholytic treatments, treating severe mental illness. The treatment protocol care had to be taken to utilize sufficiently low dosages of began with "sleep therapy", where patients were sedated the hallucinogen that the patient's ego would not be with barbiturates for a several month period, and was overwhelmed to the point where verbal analysis would followed by a "depatterning" phase of massive be inhibited. When in the course of psycholytic electroshock and frequent doses of LSD designed to psychotherapy higher dosages were utilized, the obliterate past behavior patterns. Patients were then resultant experience could no longer be contained once again heavily sedated, and subsequently subjected within the intended theoretical framework, thus to a prolonged "psychic driving" reconditioning phase necessitating delineation of an entirely new paradigm.
where they received constant auditory bombardmentfrom speakers under their pillows repeating tape The Psychedelic Treatment Model
recorded messages, with some patients hearing the same Psychiatrists utilizing the higher dose model on message repeated a quarter of a million times. Given their patients, as well as self-experimenting on the gross excesses in all modalities of this "treatment", themselves, quickly realized that they had accessed an inevitably severe neuro-psychiatric deterioration was entirely new and novel dimension of consciousness. As incurred by many of Cameron's unconsented subjects Dr. Hofmann had experienced during his own (Marks, 1979; Lee and Schlain, 1985). Ultimately, the exploration, this unexpected level of awareness could efforts of the CIA and their contract psychiatrists came alternately be rapturous or terrifying. The first to naught as their ill-advised collaboration with psychiatrist to explore this paradigm was the Canadian hallucinogens yielded little of value to support either the researcher Humphrey Osmond. Utilizing first mescal- CIA's mind control theories or the psychotomimetic ine, and later LSD, Osmond devoted his studies to the investigations of psychiatric researchers.
treatment of alcoholism, a notoriously difficult andrefractory condition. Noting that some alcoholics were The Psycholytic Treatment Model
only able to cease their pathological drinking behaviors Early experimentation in Switzerland following after they had experienced a terrifying, hallucinatory Albert Hofmann's discovery in the 1940's had discerned episode of delirium tremens during alcohol withdrawal, a phenomena quite different than that of the much Osmond set out to replicate this state through utilization heralded yet bizarre psychotomimetic mental of a high dose hallucinogen model. Observing that what experience. In subjects given a relatively low dose of distinguished his treatment successes from his treatment LSD, there appeared to occur a release of repressed failures was whether a transcendent and mystical state psychic material, particularly in anxiety states and of consciousness was attained, Osmond recognized the obsessional neuroses. By allowing this otherwise strong resemblance to states of religious conversion, repressed and threatening material to flow effortlessly bringing to mind William James' old axiom that "the into consciousness, investigators surmised that low dose best cure for dipsomania is religiomania." Dissatisfied LSD treatment could facilitate the psychotherapy with the prevailing jargon, and arguing that his model process (Stoll, 1947). Application of the low dose demonstrated that hallucinogens did much more than model in Europe as well as the United States ascertained "mimic psychosis", Osmond introduced at the 1957 that psycholytic treatment had particular value with meeting of the New York Academy of Sciences the term patients with rigid defense mechanisms and excessively psychedelic, explaining that the "mind manifesting" strict superego structures. By facilitating ego regression, state did not necessarily produce a predictable and Grob, Psychiatric Research with Hallucinogens pathological sequence of events, but rather could By the mid-1960's, the secret was out. Growing catalyze an enriching and life changing vision. And in interest in hallucinogens had catalyzed, and was presaging the cacophonous debate that would shortly catalyzed by, profound cultural shifts. Along with the fall upon the infant field of hallucinogen research, social upheaval surrounding opposition to an Osmond concluded that the psychedelic model not only increasingly unpopular war in South-East Asia, allowed us to escape "Freud's gloomier moods that hallucinogens assumed a central role in a movement persuaded him that a happy man is a self-deceiver", but that began to question many of the basic values and would soon come to the aid of humanity's imperiled precepts of mainstream Euro-American culture. The existence and "have a part to play in our survival as a populace, fueled by sensational media accounts, grew to species" (Osmond, 1957).
identify hallucinogens as a prime suspect in inciting theaccelerating state of cultural havoc. Along with the The Prohibition of Hallucinogen Research
drugs themselves, adherents of the experimental and With the evolution to the psychedelic model, treatment models became increasingly identified as part hallucinogens moved beyond the bounds of control of of the problem. Such circumstances were in no way the medical elite (Neill, 1987). No longer could they be improved by the rash pronouncements from the radical confined to investigations of a model psychosis, nor wing of what had rapidly become identified as an could they be contained within the framework of hallucinogen-inspired political movement. The leaders conventional psychiatric therapies with implicit of one notorious research group in particular drew prescribed roles for doctor and patient. By blurring the public ire and aroused anxiety and panic by such boundaries between religion and science, between proclamations as: "Make no mistake: the effect of sickness and health, and between healer and sufferer, consciousness-expanding drugs will be to transform our the psychedelic model entered the realm of applied concepts of human nature, of human potentialities, of mysticism. As word of the astounding phenomenon existence. The game is about to be changed, ladies and induced by the psychedelic model spread into the culture gentleman. . These possibilities naturally threaten at large, the inevitable backlash occurred. Horrified that every branch of the Establishment. The dangers of this extraordinary investigative probe had been external change appear to frighten us less than the peril appropriated from their control, the leaders of the of internal change. LSD is more frightening than the psychiatric profession directed harsh criticism at their Bomb!" (Leary and Alpert, 1962). irrepressible and increasingly evangelistic colleagues. In response to escalating fears that hallucinogens Roy Grinker, the first editor of the prestigious Archives had become an out of control menace to public safety of General Psychiatry, in a 1963 editorial castigated and cultural stability, the government moved to restrict those psychiatric researchers who had become access to these potent agents of change. Psychiatric preoccupied with administering "the drug to themselves, leaders, gravely concerned by the threat to public mental and some, who became enamored with the mystical health, and perhaps to their professional image as well, hallucinatory state, eventually in their 'mystique' became vehemently urged government regulating agencies to unqualified as competent investigators" (Grinker, 1963).
tighten their controls. Roy Grinker, illustrious And a year later, in the Journal of the American psychiatrist and President of the American Medical Medical Association, Grinker charged researchers with Association, issued an urgent warning to his colleagues "using uncontrolled, unscientific methods. In fact, these that greater damage lay ahead unless usage of these professionals are widely known to participate in drug hazardous chemical agents was contained. Going ingestion, rendering their conclusions biased by their beyond merely calling for the psychiatry profession to own ecstasy…The psychotomimetics are being take action against this growing peril, which would 'bootlegged', and as drugs now under scientific include denouncing the renegades within its own ranks, investigation they are being misused" (Grinker, 1964). Grinker castigated the government for having been In moving beyond the boundaries of conventional woefully lacking in vigilance and having neglected its scientific inquiry, the hallucinogens had "become duty: "The Food and Drug Administration has failed in invested with an aura of magic" (Cole and Katz, 1964), its policing functions. The drugs are indeed dangerous and thus could no longer be provided the status and even when used under the best of precautions and protection of their elite profession. The covenant had conditions" (Grinker, 1964).
been broken. The hallucinogens, along with the Driven into action by increasingly lurid media and proponents of their continued exploration, were cast out, law enforcement accounts of widespread hallucinogen becoming pariahs in a land and a time that increasingly use among the young, amidst dire warnings that this viewed them as threats to public safety and social order.
insidious threat would erode the values and work ethicof future generations, government regulators had no The Heffter Review of Psychedelic Research, Volume 1, 1998 choice but to act. In 1965 the Congress passed the Drug and shame, hallucinogen research became a non-issue, Abuse Control Amendment, which placed tight virtually disappearing from the professional literature restrictions on hallucinogen research, forcing all and educational curriculums. By the early 1970's, research applications to be routed through the FDA for psychiatric researchers and academicians had perceived approval. In April, 1966, succumbing to mounting that to continue to advocate for human research with adverse publicity, Sandoz Pharmaceuticals ceased the hallucinogens, or even to be identified with past interest marketing of what their esteemed research chemist in their therapeutic potential, might seriously jeopardize Albert Hofmann would come to call "my problem child" their future careers. Difficult decisions had to be made.
(Hoffman, 1983). Also during the spring of 1966, From the mid 1960's onward, a split began to appear in Senator Robert Kennedy called for Congressional the ranks of psychiatric hallucinogen researchers. For Hearings on the problem. Kennedy, whose wife Ethel those who would maintain their enthusiasm for the had reportedly received psychiatric treatments with potentials of these singular substances, a path of LSD, expressed concern that potentially vital research professional marginalization would follow. For those was being obstructed, questioning: "Why if they were who would take a stand against their perfidious threat, worthwhile six months ago, why aren't they worthwhile accolades and professional advancement would be now?… I think we have given too much emphasis and forthcoming. For most, however, it was to be a process so much attention to the fact that it can be dangerous of quietly disengaging, often from what had been a and that it can hurt an individual who uses it. . that passionate interest, and re-directing their careers perhaps to some extent we have lost sight of the fact that towards tamer and less disputable areas. With very few it can be very, very helpful in our society if used exceptions (Grinspoon and Bakalar, 1979; Grinspoon properly" (Lee and Schlain, 1985). Kennedy's pleas and Bakalar, 1986; Strassman, 1984), a veil of silence went unheeded, as over the next few years more and had descended over the putative role of hallucinogen more stringent restrictions were imposed on research in psychiatry.
hallucinogen research, culminating in the Bureau ofNarcotics and Dangerous Drugs (the predecessor to the The Future of Hallucinogen Research in
Drug Enforcement Agency) decision to place the hallucinogens in the Schedule I class, reserved for Where are we to go with this most unusual class of dangerous drugs of abuse with no medical value. psychoactive substances? Some would say it is best to Research ground to a virtual halt. Government, civic let sleeping dogs lie, that the hallucinogens only brought and medical leaders had all responded to their call to discord and controversy to the ranks of psychiatry and duty, permanently expunging, they hoped, what their re-examination can only lead to further turmoil President Lyndon Johnson had declared in his State of and acrimony. Psychiatry has moved far beyond the the Union address in January, 1968, "these powders time where hallucinogens were viewed as being on the and pills which threaten our nation's health, vitality and cutting edge of research investigation. Many self-respect" (Stevens, 1987). psychiatrists graduating from training programs in thelast decade are not even aware of the role hallucinogens Discounting Hallucinogen Research
once did play in the arena of legitimate research. The Hallucinogens, in the guise of an experimental conventional point of view is that these drugs are probe into the mysterious world of mental illness, had potential substances of abuse, nothing more. Within burst on the scene during the infancy of psychiatric mainstream, academic psychiatry forums for discussion research. They had not only unleashed a firestorm of of the relative merits of resuming inquiries into this area controversy as a highly touted therapeutic intervention, have been restricted. What was once a roar of often but had greatly contributed to the development of the vituperative debate has receded to barely a whisper.
exciting new specialty of laboratory neurochemistry Perhaps this twenty-five year period of quiescence research. Access to these unique agents for animal and retreat into relative obscurity has been necessary to research has been permitted to continue unimpeded, and finally give the question of hallucinogens a fair hearing.
they have contributed greatly to our understanding of We have seen in a prior epoch of investigation a playing neurotransmitter systems, brain imaging techniques and field painfully polarized between ardent advocates and behavioral pharmacology (Jacobs, 1984; Freedman, fervent foes of the hallucinogens' putative role as agents 1986). And yet, human research with hallucinogens of discovery and healing. The truth has always rested had, until now, vanished from the scene. Discounted somewhere in between the dichotomous poles of for ever having held value or potential, it is as if they panacea and toxin. The protagonists of the past, whose had never been with us. A source of embarrassment careers and integrity so often appeared to be interwoven Grob, Psychiatric Research with Hallucinogens with the content and outcome of their fierce debate, are hallucinogen research during the 1950s and 1960s, and exiting the arena. Rumblings of renewed interest are persisting as an alluring hope, has been their putative being heard within the halls of academic psychiatry. A role in alleviating mental suffering. During a mere new dialogue is slowly starting to emerge. Hopefully, fifteen year period, over a thousand clinical papers were the lessons of the past will be appreciated, and utilized published in the professional literature discussing the to forge a partnership and collaboration where divergent experiences of 40,000 patients treated with perspectives will be given a fair and open hearing, and hallucinogens (Grinspoon and Bakalar, 1979). While the true potential of the hallucinogens may finally be many of these reports were presented in the form of descriptive case studies and are attributed little value by As the sleeping giant of hallucinogen research contemporary research standards, they can help point emerges from its twenty-five year slumber, it will the way for future investigations. A wide variety of perceive that the world of psychiatry has vastly changed psychopathological phenomena were subjected to from when it was put to rest. The once reigning rulers intervention with hallucinogens, often leading to of psychoanalysis have receded to positions of relative encouraging reports of positive clinical outcomes.
obscurity as the field has become progressively Unfortunately, examining these stimulating accounts in dominated by the adherents of biological reductionism. retrospect reveals notable flaws in their design, The insights gleaned from the individual case study, including primitive and by today's standards deficient once the standard of psychoanalytic investigation, have measures designed to evaluate therapeutic change, lack been devalued and supplanted by the rigorous of outcome follow-up and unwillingness to utilize methodological research design of modern psychiatry. appropriate control subjects. As the debate over In the future, the putative value of hallucinogens in hallucinogens intensified, it also became apparent that psychiatry can no longer rest on claims deriving from from both warring camps investigators' biases (whether anecdotal case studies, as inspiring as they may be, but conscious or unconscious) were confounding their rather must evolve out of the findings of well-structured, results. From our current vantage point, it is often controlled, scientific investigation. To achieve difficult to ascertain the true significance of this past relevance and be accepted as a reputable field of study, research other than to appreciate that sufficient clinical hallucinogen research must satisfy the standards of change appears to have been catalyzed that further contemporary psychiatric research. To maintain an investigation is merited. And as we prepare to delve iconoclastic insistence that the very nature of these into the question of the hallucinogens' application to substances transcends standard research designs would treatment models, it will be essential that we control for be to prolong their marginalization and deny the the flaws that made a previous generation of research opportunity finally to explore their potential utility.
suspect. State of the art research methodology must be The knowledge base of biological psychiatry and utilized, including proper attention to set and setting, the neurosciences has exploded over the last two control populations and measures of short and long term decades, facilitated in part by probes and techniques treatment outcome. An atmosphere of active developed with hallucinogen research in animals collaboration among investigators with contrasting (Jacobs, 1984; Freedman, 1986). The potential for perspectives needs to be established, avoiding at all costs further advances in our understanding of the the schism which led to the collapse of earlier efforts. mechanisms of brain function has been recognized andenunciated at a technical meeting of the National The Relevance of the Past
Institute on Drug Abuse (NIDA) in July, 1992, that We are on the threshold of initiating explorations concluded that it is now time to move beyond pure which may have considerable ramifications for our animal research into the realm of human investigation.
future. There is much at stake and much to learn. But We are now on the threshold of initiating studies in order to take full advantage of this opportunity we utilizing state of the art research techniques, including must fully understand our past, including that which we sophisticated brain imaging scans, neuroendocrine know from cultures distant to our own place and time.
challenge tests, and receptor binding studies in human Plant derived hallucinogens once played a vital, albeit subjects. The strategy of pursuing such biological poorly appreciated role in our pre-historical lineage investigations will likely not only yield valuable new (Furst, 1976; Dobkin de Rios, 1984). While psychiatry information in the neurosciences, but facilitate the re- has traditionally held a disparaging and pathologizing legitimization of human research with hallucinogens view towards shamanic belief systems and practices and ultimately become a prelude to the re-exploration of (Devereux, 1958), evidence supplied by transcultural their effects on perception, cognition, and emotion.
anthropological investigators (Jilek, 1971; Noll, 1983) One of the most controversial arenas of The Heffter Review of Psychedelic Research, Volume 1, 1998 demonstrates that shamanic practices may actually be An Illustrative Model
conducive to high levels of psychological health and One of the most exciting areas of investigation functioning. To move beyond the commonly held from the past era of hallucinogen research was the psychiatric viewpoint that shamanism is nothing more treatment of severe, refractory alcoholism. In the 1950s than primitivism and the prehistorical wellspring of psychiatric researchers had identified the similarities mental illness, would allow for receptivity to learning between the spectrum of the LSD experience and the from a paradigm that has incorporated for thousands of phenomenology of delirium tremens (Osmond, 1957; years the utilization of hallucinogens as a vital facet of Ditman and Whittlesey, 1959). As alcoholism was belief systems and healing practices (Bravo and Grob, notorious for its lack of responsiveness to conventional 1989). If we are to assess optimally the true clinical treatment approaches, great interest and energies were efficacy and safety of the hallucinogens, it is imperative directed towards this area of study. Highly impressive that we be conscious of the critical extrapharmaco- short term results of treatment with hallucinogens logical variables that we know to be integral to the (Chwelos et al, 1959; MacLean et al, 1961; Van Dusen shamanic model. Ample attention and sensitivity must et al, 1967) gave impetus to a surge of enthusiasm that a be given to the preparation for the hallucinogen dramatic and effective intervention had finally been experience, the powerful expectation effects directed found. Additional support was forthcoming from Bill toward predetermined therapeutic goals, the formalized Wilson, the founder of Alcoholics Anonymous, who structure of the session and the integration of the altered revealed that his own carefully supervised experiences state experience in the days, weeks and months with LSD had not only been a highly valuable personal following the experience. The failure to adhere to any experience, but were also fully compatible with the of these aspects of the shamanic paradigm would be to tenets of the movement he had started (Grof, 1987). deny hallucinogen research the full opportunity to test However, as the level of discord within the psychiatric profession and the degree of alarm in the public What removes the shamanic world view so far from heightened, resistance to accepting the hallucinogen our own, and consequently presents the greatest model for alcoholism intensified. As mainstream challenges when attempting to incorporate its insights psychiatry could no longer stand idly by in the face of into contemporary research methodology, is the belief threatened radical upheaval, so the Board of Trustees of that the plant hallucinogens are sacraments of divine Alcoholics Anonymous felt compelled to reject their origin. However, it is this reverential and spiritual creator Bill Wilson's proposed endorsement.
utilization of psychoactive substances that so pointedly It soon became apparent that the methodological distinguishes the practices of tribal and shamanic shortcomings of the research alleging to demonstrate peoples from our own contemporary profaned and unequivocally positive results in the treatment of pathologized context of drug abuse. Hallucinogens in alcoholism would undermine progress in the field.
the shamanic world have traditionally played a critical Poorly controlled research design, with questionable role in rites of initiation, providing personal measures of change and inadequate follow-up led to regeneration and radical change, and are perceived as charges that hallucinogen advocates had been blinded essential to the process of growth and maturity and the by their own enthusiasm and had mis-interpreted and acquisition of meaning (Grob and Dobkin de Rios, mis-represented their findings. Opponents of the 1992; Zoja, 1989). They are not mis-used or abused, hallucinogen treatment model would subsequently and are not agents of societal chaos and destruction.
conduct their own clinical trials, designed to refute what Their use is fully sanctioned and integrated into the they perceived as dangerous and exaggerated claims of mainstream of society, and commonly utilized in therapeutic success (Smart et al, 1966; Hollister et al, ritually prescribed and elder facilitated ceremonies. The 1969; Ludwig, Levine and Stark, 1970). These studies, hypersuggestible properties of the hallucinogens, which purported to demonstrate an entire lack of utilized within a highly controlled set and setting, treatment efficacy of models utilizing hallucinogens, achieves a powerful effect, reinforcing cultural cohesion were received by the psychiatric establishment with and commitment. These apparent beneficial effects of great relief. In fact, the Ludwig, Levine and Stark study shamanic hallucinogen use contrast markedly with the provided such reassurance to a profession so shaken by destructive outcomes often observed in our own its own iconoclasts, as well as satisfying contemporary contemporary contexts (Dobkin de Rios and Grob, formal medical research standards with such aplomb, that it was awarded the prestigious Lester N. HofheimerPrize for Research from the American PsychiatricAssociation. Grob, Psychiatric Research with Hallucinogens Nevertheless, the investigations designed to provide Native American Church is a clear contemporary the last word on the "failed" hallucinogen treatment example of the successful application of the shamanic model have themselves come under scathing attack. model to the treatment of severe, refractory illness.
Not only have the investigators' lack of appreciation of Although the Native American Church applies to a set and setting, failure to adequately prepare their circumscribed and relatively homogenous population, it patients for the experience and refusal to allow for provides a valuable lesson on the importance of the follow-up integration been identified (Grinspoon and shamanic model and the need for attentiveness to set Bakalar, 1979), but the capricious nature of medical and setting, intention, preparation and integration, as research has itself been implicated. "At a time when well as group identification. If we are to develop LSD was popular, Levine and Ludwig (1967) had optimal research designs for evaluating the therapeutic reported positive results… When LSD fell out of favor utility of hallucinogens, it will not be sufficient to adhere and the positive results became politically unwise, they to strict standards of scientific methodology alone. We obtained negative results. Unconsciously or consciously must also pay heed to the examples provided us by such they built into their study a number of antitherapeutic successful applications of the shamanic paradigm. It elements that guaranteed a therapeutic failure" (Grof, will only be then, when we have wedded our state of the art research designs to the wisdom accrued from the The discussion of the potential role of past, that we will adequately appreciate what role hallucinogens in the treatment of alcoholism, and by hallucinogens may have in our future.
inference its application to other psychiatric disorders aswell, would not be complete without an examination of the role of the plant hallucinogen, peyote, in the After a twenty-five year period of virtual treatment of Native American Indians. Evidence exists prohibition, formal psychiatric research with that peyote was in widespread use in Central America hallucinogenic drugs has resumed. This article has and revered as a medicine and religious sacrament as reviewed the process by which hallucinogens came to be early as 200 B.C. (Furst, 1976). After the American viewed as beyond the pale of respected and sanctioned Civil War, the use of peyote moved north of the Rio clinical investigation, and has directed attention to the Grande River and quickly spread to dozens of native importance of fully understanding the lessons of the past tribes throughout the United States and Canada. During so as to avoid a similar fate for recently approved the 1870s and 1880s a peyote vision religion developed research endeavors. The shamanistic use of in reaction to the inexorable encroachment of non- hallucinogenic plants as agents designed to facilitate native peoples onto the Indian lands and the associated, healing, acquire knowledge and enhance societal deliberate destruction of native culture. With the defeat cohesion were brutally repressed in both the Old and and subjugation of the Native American people, New Worlds by the progenitors of our own alcoholism became epidemic. Although until recently contemporary Euro-American culture, often with faced with unrelenting political repression by the U.S.
complicity of the medical professions. Knowledge of government, the Native American Church, a syncretistic the properties and potentials of these consciousness church combining elements of traditional Indian altering plants was forgotten or driven deeply religion and Christianity and utilizing peyote as its underground for centuries. It was not until the late ritual sacrament, has been recognized by 1800s that German pharmaceutical researchers anthropologists and psychiatrists as being the only investigating the properties of peyote re-discovered the effective treatment for endemic alcoholism (Schultes, profound and highly unusual effects of these substances.
1938, La Barre, 1947, Bergman, 1971, Albaugh and A dispute anticipating the virulent controversies of the Anderson, 1974). Karl Menninger, a revered figure in 1960s ensued, however, pitting proponents of this new the development of American Psychiatry in the 20th model of consciousness exploration against those who Century, has stated: "Peyote is not harmful to these questioned the propriety of their colleagues enthusiasm people; it is beneficial, comforting, inspiring, and for self experimentation and penchant for sweeping appears to be spiritually nourishing. It is a better proclamations. The history of hallucinogen research in antidote to alcohol than anything the missionaries, the the 20th century has revolved around this regrettable white man, the American Medical Association, and the polarization, and as such has impeded the evolution of public health services have come up with" (Bergman, Developments in the second half of the 20th Integral to the positive treatment outcome with century were catalyzed by the remarkable discoveries of peyote has been its sacramental utilization within the the Swiss research chemist, Albert Hofmann. In the ritual context of mystical-religious experience. The The Heffter Review of Psychedelic Research, Volume 1, 1998 wake of his synthesis of the extraordinarily potent fascinating yet poorly understood class of psychoactive psychoactive substance, lysergic acid diethylamide, a substances. Whether we can successfully take period of active investigation ensued. Notable gains advantage of this opportunity will depend ultimately on were accomplished utilizing the psychotomimetic model how well we have learned the lessons of the past.
for understanding mental illness and the low dosepsycholytic approach for the treatment of a variety of psychiatric conditions. It soon became apparent Albaugh, BJ (1974) Peyote in the treatment of however, that these models possessed inherent alcoholism among American Indians. Am J limitations when applied to the orthodox psychiatric Psychiatry 131, 1247-1250. constructs then in vogue. The implementation of the Bergman, RL (1971) Navajo peyote use: Its apparent high dose psychedelic model, in spite of its apparent safety. Amer J Psychiatry 128, 695-699.
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A slightly abbreviated version of this article first appeared in the Yearbook for Ethnomedicine and the Study of Consciousness 3:91- 3. Recent Advances and Concepts in the Search for Biological
Correlates of hallucinogen-induced Altered States of Consciousness
Franz X. Vollenweider, M.D.
intrusive mental activity. Specifically, the CSTCloop model suggests that a deficient thalamic "filter" Hallucinogens and related substances constitute function leads to sensory overload of the cortex a powerful experimental basis to investigate which in turn results in cognitive fragmentation and biological correlates of altered states of sensory flooding as seen in hallucinogen-induced consciousness (ASC) (Hermle et al. 1988; Javitt and states and naturally occurring psychoses Zukin 1991; Vollenweider, 1994). In combination with functional brain imaging techniques and The theoretical conception of the "thalamic pharmacological methodologies, they are remarkable filter" theory is comparable to animal models of molecular probes to study the functional sensory gating deficits such as the prepulse organization of the brain and to generate chemical inhibition paradigm (PPI), although the PPI hypotheses of ASC. The study of hallucinogens in paradigm does not explicitly refer to the thalamus as humans is important because these substances affect an anatomical structure responsible for filtering a number of brain functions that typically deficits. However, both the CSTC model and the characterize the human mind, including cognition, PPI paradigm suggest that perturbations in cortico- volition, ego, and self-consciousness. They can elicit striato-thalamic pathways are critical for the loss of a clinical syndrome that resembles in various aspects inhibition processes and the pathogenesis of the first manifestation of schizophrenic disorders, psychotic symptoms. This assumption is supported but is different in other respects (Fischman, 1983; by increasing preclinical evidence demonstrating Gouzoulis et al. 1994; Vollenweider et al. 1997d).
that hallucinogens specifically interfere with The various forms of ego-disorders are especially neurotransmitter systems within the limbic cortico- prominent features of psychedelic and naturally striatal-thalamic circuitry and produce PPI-deficits occurring psychoses. For example, they can produce comparable to those seen in several neuropsychiatric a form of ego-dissolution that is experienced with disorders characterized by failure to inhibit heightened awareness, en-hanced introspection, irrelevant cognitive, motor or sensory information.
sublime happiness, as well as a form that is Positron emission tomography (PET) was used experienced with anxiety and fragmentation. Hence, to test the hypothesis that hallucinogens may lead to studies of the neuronal mechanisms of action of a disruption of "filter" functions and produce a hallucinogens should provide not only novel insights sensory overload of the frontal cortex. Moreover, a into the pathophysiology of psychiatric disorders and correlational analysis between hallucinogen-induced their treatments, but in a more wider sense into the changes in neuronal activity and specific dimensions biology of consciousness as a whole, e.g. into the of ASC was carried out to elucidate the neuronal biology of ego structuring processes.
substrates of psychedelic states. Psychometric In the present discussion, I wish to summarize measures and PET investigations with specific some of the recent advances in hallucinogen research receptor ligands were and are performed to that have resulted from human studies conducted in investigate the effects of hallucinogens on brain our group. In the first part, a human model of functions before and after pretreatment with specific sensory gating deficits, the cortico-striato-thalamo- neuroreceptor antagonists. These studies provide a cortical (CSTC) loop model of psychosensory paradigm shift where interactions of different processing, is introduced to provide a perspective on neurotransmitter systems are seen as the basis for the how current scientific knowledge about hallucinogen psychological effects of hallucinogens. The PPI drug action could be visualized within a synthetic paradigm is used as a second measure to characterize framework to explain their subjective effects in the putative effects of hallucinogens on inhibition humans. The CSTC model is based on the processes in humans and functional interactions of assumption that psychedelic and psychotic symptoms neurotransmitter systems in ASC. Clearly, among can be conceptualized by failure to inhibit or "gate" the many topics that could be considered in this Vollenweider, Hallucinogen-induced altered states context, I have to make some selection, and some ofthe subjects unavoidably will remain sketchy.
APZ scores (mean)
Figure 1. APZ Profiles in healthy volunteers (n = 20). Measurement of psychological dimensions of ASC
second dimension "dread of ego-dissolution"(AIA) In the context of the present theme -relating measures thought disorder, ego-disintegration, loss psychological and biological effects of of autonomy and self-control variously associated hallucinogens- the assessment and characterization with arousal, anxiety, and paranoid feelings of being of altered states of consciousness (ASC) is of endangered. The third subscale "visionary restructur- fundamental importance. Among several rating alization"(VUS), refers to auditory and visual scales, the APZ questionnaire, which has become illusions, hallucinations, synaesthetic phenomena, as the standard in Europe for measuring specific states well as to changes in the meaning of various of consciousness and which has been used on a routine basis by our group, is to be described. In The intercultural consistency of the APZ short, the APZ questionnaire was developed based on dimensions OSE, AIA and VUS has been rigorously a large prospective study done with 393 subjects tested in a subsequent study, the International Study tested with cannabinoids, dimethyltryptamine, on Altered States of Consciousness (ISASC), and the psilocybin, mescaline, harmaline, nitrosoxide, dimensions have been shown to be altered con- hypnosis, autogenic training, and meditation sistently in a manner that is independent of the techniques (Dittrich, 1994). It measures three particular treatment, disorder, or condition that led primary and one secondary etiology-independent to the ASC (Dittrich et al. 1985; Dittrich, 1994). The dimensions of ASC. The first dimension, designated APZ rating scale is now available in an English as "oceanic boundlessness" (OSE), measures version and it is important to emphasize the need for derealization phenomena and ego-dissolution which a quantitative instrument such as the APZ to are associated with enhanced sensory awareness and exchange and integrate further research into the a positive basic mood ranging from heightened effects of hallucinogens on an international level.
feelings to sublime happiness and exaltation. Ego- So far, the APZ questionnaire has been used to dissolution can include or start with a mere characterize the psychological effects of hallucino- loosening of ego-boundaries, but may end up in a gens, dissociative anesthetics, stimulants, and feeling of merging with the cosmos, where the entactogens. For example, using the APZ experience of the sense of time is changed or questionnaire, we recently demonstrated in a double- completely vanished. This state might be comparable blind placebo-controlled study that the psychological to a mystical experience, if fully developed. The effects of MDMA in normals can be clearly differ- The Heffter Review of Psychedelic Research, Volume 1, 1998 entiated from those seen in comparable studies with Cortico-striato-thalamo-cortical feedback loops (CSTC)
sensory assoc. cortex
1st proj. area
ketamine blocks NMDA receptors psilocybin activates 5-HT2 receptors Figure 2. Cortico-striato-thalamo-cortical feedback loops. ketamine, psilocybin, and amphetamine what was typically described was an intensification (Vollenweider et al. 1997e) (Figure 1).
of sensory perception ("colors were more intense," As seen in figure 1, MDMA (1.7 mg/kg p.o.) "objects appeared more detailed," sound was more produced a unique pattern of APZ scores. Although clear, etc.), and visual illusions ("3D-vision of flat the OSE scores in MDMA subjects were approx- objects," micropsia and macropsia, etc.). Finally, imately similar (80%) to those seen after psilocybin with regard to psychostimulants, euphorigenic doses and ketamine, the VUS and AIA scores were only of d-amphetamine produced similar AIA scores, but about 30-50% of the values seen in psilocybin and lower OSE and VUS scores than those seen in the ketamine subjects (Vollenweider et al. 1997b; study with MDMA (Vollenweider et al. 1997a).
Vollenweider et al. 1997b). In contrast to psilocybin Although additional studies using multiple doses are and ketamine subjects, loosening of ego-boundaries needed to confirm these conclusions, the present and perceptual changes produced by MDMA were findings are suggestive of appreciable differences in generally not experienced as problematic or the psychological profiles produced by MDMA psychotic fusion, but instead as a positive or relative to psilocybin, ketamine, or d-amphetamine.
pleasurable state in which the distinction between Certainly, several types of ASCs possibly may self and nonself was reduced and a sense of have etiology-specific dimensions, e.g. acoustic- enhanced empathy existed. Furthermore, MDMA hallucinatory phenomena, memory disturbances etc., subjects noted that this state allowed them to feel besides those mentioned above. The identification of "more united with the world" and less "separated such specific dimensions will be pertinent to a more from others". Unlike psilocybin and ketamine, both comprehensive description of ASC's. Moreover, of which produced comparable increases in since individual reaction differences on ASC- hallucinations as indicated by the VUS scores, inducing agents are high, even when experimental MDMA did not produce hallucinations, but instead conditions are kept constant, research into other Vollenweider, Hallucinogen-induced altered states factors such as personality traits, genetic The model includes the view that the thalamus predispositions, environmental factors, etc., acts a filter or gating mechanism for the extero- and influencing the course of ASC is mandatory. Such interoceptive information flow to the cerebral cortex studies were performed (Dittrich, 1994) or are in and that deficits in thalamic gating may lead to a progress (Vollenweider et al., in preparation).
sensory overload of the cortex, which in turn may Another important need, particularly for exploring ultimately cause the sensory flooding, cognitive pathophysiological commonalties of ASC and fragmentation and ego-dissolution seen in drug- naturally occurring psychoses, is the systematic induced altered mental states and psychotic assessment of similarities and differences of disorders. The filter capability of the thalamus is psychotic symptoms seen in drug-induced ASC and thought to be under the control of cortico-striato- psychiatric patients, using the same psychometric thalamic (CST) feedback loops. Specifically, it is instruments, e.g. such as the APZ, HRS or IPP rating hypothesized that the striatum, comprising the dorsal scales (Dittrich, 1994; Scharfetter 1995; Strassman, and the ventral striatum (including the nucleus accumbens) and the corresponding dorsal andventral pallidum, excerts an inhibitory function on The CSTC model of sensory information
the thalamus. Inhibition of the thalamus should processing and ASC
theoretically result in a decrease of sensory input to Based on the available neuroanatomical the cortex and in a reduction of arousal, protecting evidence and pharmacological findings of the cerebral cortex from sensory overload and psychedelic drug actions, we proposed a cortico- breakdown of its integrative capacity. The model subcortical model of psychosensory information suggests that striatal activity is modulated by a processing that can be used as a starting working number of subsidiary circuits, with their respectively hypothesis to analyze and integrate the effects of neurotransmitter systems. The mesostriatal and different chemical types of hallucinogens at a system mesolimbic projections provide an inhibitory level. The model conceptualizes psychedelic states as dopaminergic input to the striatum including the complex disturbances that arise from more nucleus accumbens. Under physiological conditions, elementary deficits of sensory information the inhibitory influence of dopaminergic systems on processing in cortico-striato-thalamo-cortical the striatum is, however, thought to be counter- (CSTC) feedback loops. The model was not entirely balanced by the glutamatergic excitatory input from new; it incorporates the idea that psychotic cortico-striatal pathways. This assumption implies symptoms might relate to a dopaminergic and/or that an increase in dopaminergic tone, as well as a decrease in glutamatergic neurotransmission should dysbalance in mesolimbic and/or mesolimbic- theoretically lead to a reduction of the inhibitory corticostriatal pathways, but it enlarges this influence of the striatum on the thalamus and result hypothesis, insofar as serotonergic and GABAergic in an opening of the thalamic "filter" and, neurotransmission are also brought into the scheme subsequently, in a sensory overload of the cerebral (Vollenweider, 1992; Vollenweider, 1994).
cortex, resulting in psychotic symptom formation.
In short, five CSTC loops have been identified Finally, the reticular formation, which is activated by and each loop, functioning in parallel, is thought to input from all sensory modalities, gives rise to mediate a different set of functions; the motor, the serotonergic projections to the components of the oculomotor, the prefrontal, the association and the CST loops, namely the frontal cerebral cortex, limbic loop. The limbic loop is involved in memory, cingulate cortex, hippocampus, striatum, nucleus learning, and self-nonself discrimination by linking accumbens, thalamus, and amygdala. Excessive of cortical categorized exteroceptive perception and activation of the postsynaptic elements of these internal stimuli of the value system. The limbic loop serotonergic projection sites should also result in a originates in the medial and lateral temporal lobe reduction of the thalamic gating mechanism and, and hippocampal formation, projects to the ventral consequently, in a sensory overload of frontal cortex striatum including the nucleus accumbens, the resulting in psychosis.
ventromedial portions of the caudate nucleus andputamen. Projections from these nuclei then First results testing the CSTC model
converge on the ventral pallidum and feedback via Although the CSTC model is an oversimpli- the thalamus to the anterior cingulate and the fication, it provides a set of testable hypotheses.
orbitofrontal cortex (Figure 2).
Specifically, according to the CSTC model we have The Heffter Review of Psychedelic Research, Volume 1, 1998 hypothesized, the reduction of glutamatergic serotonergic system, for example by the mixed functions, for example by the NMDA antagonist 5-HT2A/2C/1A agonist psilocybin, should lead to ketamine, should lead to a sensory overload and activation of the frontal cortex similar to that seen metabolic activation of the cerebral cortex, with ketamine (see figure 2).
presumably of the frontal cortex (hyperfrontality). Ifthe CSTC model is valid, stimulation of the u Factor I: frontomedial, frontolateral, cingulate ant. and post., parietal, and sensorimotor Cortex u Factor II: occipitomedial and -lateral Cortex u Factor III: temporomedial and lateral Cortex u Factor IV: caudate nucleus, putamen u Factor V: thalamus Figure 3. Five clusters of brain regions (factors 1-5) that can be interpreted as functional "units" or "modules."Each unit comprises a number of functionally highly intercorrelated brain regions. For example, the "fronto-parietal factor"(I)includes the frontomedial, frontolateral, anterior and posterior cingulate, parietal, andsensorimotor cortex. The integrity of this factor structure is not disrupted in ASC, but the activity of brain regionswithin such an unit alters with psychedelic states. The "fronto-parietal factor" appears to play a fundamental roleas a "central supervision and execution system" insofar as this unit is involved in ego-structuring processes andself-representation by interpretation and integration of extra- and intrasensory information, planning andexecution of motor functions. The hyperfrontality hypothesis of ketamine- and crease of metabolic activity in the frontal cortex psilocybin-induced mental states has been tested in including the anterior cingulate, and also with healthy volunteers using positron emission changes in the temporal cortex and basal ganglia.
tomography (PET) and the radioligand [18F]fluoro- These findings demonstrated that not a single brain deoxyglucose (FDG). PET with FDG enables one to region, but distributed neuronal networks are explore directly the interactive organization of the involved in psychedelic and psychotic symptom human brain, via the coupling of cerebral glucose metabolism and neuronal activity. In fact, the central Nevertheless, the hyperfrontality finding hypothesis of a frontocortical activation in psyche- observed in these studies is potentially important.
delic states could be confirmed. Both ketamine and First, the marked stimulation of the frontal cortex, psilocybin led to a marked metabolic activation of the anterior cingulate, the temporomedial cortex and the frontal cortex and a number of overlapping the thalamus seen in both psilocybin and ketamine metabolic changes in other brain regions subjects is in line with the thalamic filter theory, (Vollenweider et al. 1997c; Vollenweider et al.
suggesting that a disruption of the limbic cortico- 1997d). To elucidate the relationship between striato-thalamic (CST) loop should theoretically lead regional metabolic activation of the brain and to a sensory overload of the frontal cortex and its specific states of consciousness a correlational limbic relay stations. This interpretation is also analysis was performed. One of the main findings of supported by the recent finding that ketamine this computation was that ego dissolution and administration in haloperidol-stabilized schizo- derealization phenomena correlated with the in- phrenics resulted in an increase of cerebral blood Vollenweider, Hallucinogen-induced altered states flow in the thalamus, frontomedial and anterior computed. Surprisingly, this computation revealed cingulate cortex, concomitant with the exacerbation that the "cortical-subcortical organization" (based on of psychotic symptoms (Lahti et al. 1995). Second, a five-factor solution) during ASC was very similar the hyperfrontality is of particular interest because it to that seen under placebo condition, indicating that appears to parallel similar findings in acutely ill the functional integrity of interrelated brain regions schizophrenic and non-schizophrenic psychotic (factors), which might be interpreted as functional patients, but contrasts with the hypofrontality finding "units" or "modules", is not disrupted in ASC (see seen in chronic schizophrenics. Third, the common Figure 3). According to their content, the factors hyperfrontality finding also supports the idea that the were labeled "fronto-parietal cortex," "temporal psychedelics used in these studies may mediated cortex," "occipital cortex," "striatum" (which their effects through a common neurotransmitter included the nucleus caudate and putamen), and system. As 5-HT2 and NMDA receptors have been "thalamus." Subsequent comparison of the factor located on GABAergic neurons in the frontal cortex, score values of the drug and placebo condition GABAergic neurons in cortico-striatal pathways may revealed, however, that subjects during hallucinatory provide a common anatomical substrate involved in states had significantly higher scores on the "frontal- the genesis of ketamine- and psilocybin-induced parietal" and "striatal" network, and lower scores on hyperfrontality and psychosis. On the other hand, the "occipital cortex" than in resting states. This both psilocybin and ketamine have been reported to finding indicates that neuronal activity within these activate either directly or indirectly the dopaminergic modules (factors) and the more global relationship system. As activation of dopaminergic pathways between these units (factors) is markedly different in could theoretically lead to disruption of the infor- ASC than in the normal waking state.
mation flow in CST-loops, the possibility remains Moreover, multiple regression analysis between that dopamine also contributes to the psychological scores (APZ scores) and factor score pathophysiology of hyperfrontality and acute values (normalized metabolic activity) revealed first psychotic symptom formations (Kehr, 1977; Meltzer that the dimension OSE (oceanic boundlessness) et al. 1978; Meltzer et al. 1981; Hiramatsu et al.
relates to changes in metabolic activity in the 1989). Certainly, such hypotheses need substantial frontal-parietal, temporal, and occipital cortex.
prospectively acquired corroborative evidence and Second, that VUS (visionary restructuralization carefully designed mechanistic studies (see below).
including hallucinatory phenomena) is associatedwith metabolic alterations of a fronto-parietal, Patterns of cortical activity in Altered states of
temporal, striatal, and occipital network, and third that anxious ego-disintegration (AIA) is primarilyassociated with metabolic changes in the thalamus, The correlational analysis between cortical as shown by the following regression equations: activity and psychological dimensions of ASC of ourpsilocybin and ketamine studies clearly indicated OSE = 0.32 F1* - 0.20 F2* + 0.11 F3 + 0.20 F4* that complex neuronal networks are involved in the formation of ASC. This implies that a multivariateanalysis of metabolic and psychological data and VUS = 0.20 F1* - 0.27 F2* + 0.17 F3* + 0.32 F4* relatively large sample size, e.g. 50 -100 subjects, is mandatory to identify the common neuroanatomicalsubstrates of ASC with accurate precision.
AIA = 0.00 F1 + 0.09 F2 + 0.01 F3 + 0.17 F4 Therefore, a number of additional placebo-controlled FDG-PET experiments with S-ketamine, R-ketamine, and amphetamine were performed in F1 is the fronto-parietal factor, F2 is the normal subjects to explore further the relationship occipital factor, F3 is the temporal factor, F4 is between hallucinogen-induced patterns of cortical the striatal factor, and F5 is the thalamic activity and the psychological dimensions of ASC factor; *denotes significance at the level of p < (Vollenweider et al. 1997; Vollenweider et al.
1997b). To identify the interactive organization ofthe brain in resting states and ASC, normalized The present results suggest that hallucinogens in metabolic PET data from placebo and corresponding combination with functional brain imaging drug conditions were subjected to a factor analysis techniques (PET, SPECT, fMRI etc.) are promising and factor scores for each individual subjects was research tools for exploring the biological correlates The Heffter Review of Psychedelic Research, Volume 1, 1998 of ego-structuring processes. It appears that the more based on an aggregation of observations over time positively experienced form of ego-dissolution (OSE) (APZ ratings, metabolism) and space (brain regions) can functionally and metabolically be differentiated though probably correct in the order of magnitude, from the more fragmented and anxious ego- might be inadequate at a finer level of resolution. To dissolution AIA. The present data also indicate that explore further the circuitry dynamics of the CSTC the CSTC model used here provides a satisfactory model during ASC, we have started making use of a starting point to approach the functional new three dimensional EEG-based functional brain organization of the brain in ASC. It should be noted, however, that the present correlations, which are Chemical Network in ASC Figure 4. Chemical Network in Altered States of Consciousness (see text). graphy for localizing the electric activity in the the treatment and pathogenesis of schizophrenia brain, which is called LORETA (low resolution (Carlsson and Carlsson 1990; Vollenweider et al.
electromagnetic tomography) (Pasqual-Marqui et al.
1997d). Indeed, both indoleamine (psilocybin, LSD) 1994). LORETA allows locating differences in the and phenylalkylamine (mescaline, DOI) hallucino- distribution of electrically active neuronal popula- gens, which produce schizophrenia-like syndromes tions with the advantage of the high time resolution in humans, primarily bind to 5-HT1, 5-HT2, 5-HT5 of the EEG. A first aim of an ongoing study is to and 5-HT7 receptors in various animal tissue explore the course of the functional relationship preparations (Peroutka, 1994). Furthermore, it has between the thalamus and cortical regions, been suggested that the common effects of these two particularly the frontal cortex, during MDMA or classes of hallucinogens may be mediated by agonist psilocybin administration in healthy volunteers actions at 5-HT2 receptors: first, because the potency (Vollenweider, Gamma and Frei, in preparation). It of hallucinogens correlates with 5-HT2 receptor is proposed that the combination of LORETA and binding affinity in animals (Titeler et al. 1988); and PET will bring further insight into the functional second, because the behavioral effects of organization of the brain in ASC.
hallucinogens in animals can be blocked by 5-HT2antagonists (Sanders-Bush et al. 1988; Meert et al.
1989; Wing et al. 1990; Schreiber et al. 1995).
Further explorations into the role of serotonin and
Furthermore, the affinity of LSD for D dopamine in ASC
(Watts et al. 1995) and other influences of The CSTC model suggests that serotonergic hallucinogens on dopamine (DA) functions (Smith et pathways modulating cortico-striatal-thalamic loops al. 1975; Haubrich and Wang 1977) suggest some of sensory and cognitive information processing are contribution of DA systems to hallucinogen effects.
critical to hallucinogenic drug action, as well as for The role of the serotonin and dopamine systems in Vollenweider, Hallucinogen-induced altered states the generation of hallucinogen-induced ASC has hallucinogen-assisted psychotherapy, specific 5-HT2A never been systematically tested in human studies.
antagonists may also prove valuable to antagonize With respect to understanding and development of prolonged or unwanted side effects of indole novel pharmacological treatments of psychoses, human studies are, however, essential, particularlysince more recent data indicate that some animal models of hallucinogenic drug action may not reflect hallucinogenic properties in man (Koerner and Appel 1982).
To test the hypotheses that 5-HT2 and/or DA D2receptors contribute to hallucinogen action in humans, we studied the influences of pretreatment with the preferential 5-HT 2A antagonist ketanserin AIA score (t-trans) (Hoyer and Schoeffter 1991), the D2 antagonist haloperidol (Burt et al. 1976), or the mixed 5-HT 2/D2 antagonist risperidone (Leysen et al. 1996) on the psychological and cognitive effects of ketanserin risperidone haloperidol psilocybin in normal subjects, using a placebo-controlled, within-subject design (Vollenweider et al.
Figure 5. Placebo (pl) and psilocybin (psi) effects 1996). The APZ rating scale and a on AIA scores. Pretreatment with the selective 5- neuropsychological test were used to assess the HT2A receptor antagonists ketanserin (k1, k2) and subjective effect of psilocybin and putative working risperidone (r1, r2) significantly blocks psilocybin- memory deficits. As seen in figure 5, the subjective induced increased AIA scores, while haloperidol (h) effects of psilocybin were blocked dose-dependently markedly increased the cognitive deficits and by the serotonin 5-HT2A antagonist ketanserin or the anxious ego-dissolution score. atypical antipsychotic risperidone, but wereincreased by the dopamine antagonist and typical Whether psilocybin increases dopaminergic antipsychotic haloperidol. These data are consistent activity through 5-HT2 receptor stimulation alone or with animal studies and provide the first evidence in in combination with 5-HT1 receptors or via another humans that psilocybin-induced ASC's are primarily receptor system needs to be further investigated and due to serotonin 5-HT2A receptor activation. Given is the main scope of an ongoing PET study on the evidence that psilocybin does not act directly serotonin-dopamine interactions (Vollenweider et al.
upon DA receptors (Creese et al. 1975) and the fact 1997g). The clarification of this issue is important, that haloperidol partially ameliorated the OSE score since more recent studies suggest that atypical including positively experienced derealization and neuroleptics mediate their antipsychotic effects depersonalization phenomena, but markedly through 5-HT2 and D2 antagonism (Meltzer and increased cognitive deficits and anxious ego- Gudelsky 1992).
dissolution as measured by the AIA score, it appearsthat psilocybin also has a complex indirect influence The sensorimotor gating model and ASC
on dopaminergic systems (Figure 4, 5). Nevertheless, Another important research concept that allows our results show that 5-HT2A/C receptor activation one to explore the neuropharmacology of hallucino- can lead to psychotic symptoms that do not depend gens and cognitive and sensorimotor gating or on DA systems. This finding together with our "filtering" deficits in ASC is the prepulse inhibition previous observation that psilocybin stimulates paradigm of the startle response (PPI) (for review see frontocortical glucose metabolism in normals (Swerdlow et al. 1992; Geyer and Markou 1995).
(Vollenweider et al. 1997d) similar to that seen in The PPI paradigm is based on the observation that a acutely ill schizophrenic patients, supports the startle response to an intensive stimulus is inhibited hypothesis that excessive serotonergic activity may or gated when the startling cue is preceeded 30-500 be a critical factor in psychedelic and naturally msec earlier by a weak prepulse. Theoretically, and occurring psychoses, at least in a subset of as similarly proposed by the CSTC loop model, schizophrenic patients, and that specific 5-HT2A impairments in inhibition processes lead to sensory antagonists may be useful in normalizing such overload, attentional deficits, and cognitive frag- imbalances (Meltzer, 1991). With respect to mentation. PPI has been used as an operational The Heffter Review of Psychedelic Research, Volume 1, 1998 measure of cognitive and sensorimotor gating in unlike hallucinogens, do not produce hallucinations both human and animal studies. PPI deficits have or psychotic symptoms in man.
been found in patients with schizophrenia, obsessive To explore and compare the putative effects of a compulsive disorder (OCD), Huntington's disease, typical indoleamine hallucinogen and entactogen on and psychosis-prone normals compared to normals, PPI, we have begun to investigate the effects of reflecting failure to gate sensory, cognitive, or motor psilocybin, a 5-HT2 agonist, and MDMA, a 5-HT information (Geyer et al. 1990; Swerdlow et al.
releaser, on PPI of acoustic startle in normal 1994; Swerdlow et al. 1995). More importantly, the laboratory rats versus healthy human volunteers (a PPI deficits seen in these psychiatric patients can be collaboration with Mark Geyer, UCSD) mimicked in rats treated with hallucinogenic 5-HT (Vollenweider et al. 1997e). To illustrate the need of agonists (psilocybin, DOI, etc.) or NMDA antag- such comparison studies, the major results of the onists (ketamine, PCP, or MK 801), giving support MDMA study shall briefly be given here. Based on to the idea that the sensory flooding seen in ASC and previous studies in rats and mice, the hypothesis was psychotic patients may have a common underlying that MDMA would disrupt PPI in both rats and neurobiological basis (Mansbach and Geyer 1989; Sipes and Geyer 1994) (see above). In fact, the Surprisingly, our preliminary data indicate that similarity of PPI deficits in animal studies and MDMA produces opposite effects on PPI in animals schizophrenic patients, in combination with other and humans: (1) MDMA decreased PPI of acoustic findings, has revitalized interest in hallucinogens in startle in a dose-related fashion in rats, as expected the 1990s and prompted a concerted search into the from previous studies; and (2) a typical recreational neurotransmitter systems involved in modulating PPI dose of MDMA (1.7 mg/kg) increased PPI measured in rodents (for review see Geyer and Markou 1995).
under comparable conditions. The multiple doses of Studies into the PPI-disruptive effects of MDMA used in rats ranged from the same 1.7 hallucinogens and related drugs contributed to the mg/kg dose used in humans to one order of development of specific hypotheses about the magnitude higher, in keeping with the typical primary locus that may be responsible for the differences in effective doses between these species.
psychological effects of hallucinogens in humans.
The dose of MDMA used in the human study was For example, animal studies subsequently shown to have substantial psychological effects in demonstrated that the PPI-disruptive effects of both the same subjects, characterized by an easily hallucinogenic 5-HT2 agonists, such as DOI (Sipes controlled affective state with feelings of relaxation, and Geyer 1995a; Sipes and Geyer 1997a) and heightened mood, euphoria, increased sensory serotonin (5-HT) releasing compounds, such as awareness, and elevated psychomotor drive, as MDMA ("Ecstasy"), could be blocked with selective detailed elsewhere (Vollenweider et al. 1997f).
5-HT2A antagonists (Padich et al. 1996). These The time between administration and testing findings gave substantial support to the idea that was selected to be at or near the time of peak effects indole- and phenylethylamine hallucinogens, but observed in rats and humans, given the respective presumably also "entactogens" such as MDMA may routes of administration (subcutaneous injection vs mediate their psychological effects in humans oral). Thus, despite attempts to maximize the through action at a common site, 5-HT2A receptors, comparability of the tests in rats and humans, although other subtypes of serotonin receptors are MDMA produced opposite behavioral effects in rats also implicated in the modulation of PPI (Sipes and versus humans, using a measure of sensorimotor Geyer 1994; Sipes and Geyer 1995; Sipes and Geyer gating that is thought to have a high degree of cross- species homology (Geyer and Markou 1995). In the The hypothesis that indoleamine hallucinogens absence of mechanistic studies, no firm conclusions such as psilocybin mediate their psychedelic effects can be drawn regarding the mediation of the primarily via 5-HT2 receptor activation has been observed MDMA effects in humans. Hence, confirmed more recently in a human study (see considerably more research will be required to above, (Vollenweider et al. 1996)). However, determine whether this disparity between drug whether and how indoleamine hallucinogens and effects in rats and humans reflects a species-specific entactogens affect PPI in humans, has not yet been difference in the mechanism of action of MDMA or tested. Moreover, it is unclear whether the 5-HT2 in the behavioral expression of a similar receptor system contributes to the psychological pharmacological effect, or both. Furthermore, these effects of entactogens in humans, since entactogens, findings demonstrate the importance of conducting Vollenweider, Hallucinogen-induced altered states mechanistic studies of pharmacological agents in biological comparison. Schizophrenia Bull 9:73- healthy humans as well as in experimental animals.
Geyer MA, Swerdlow NR, Mansbach RS, Braff DL.
(1990): Startle response models of sensorimotor In conclusion, the present data indicate that gating and habituation deficits in schizophrenia.
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[Abstract] WPA-Abstractbook: 116 Vollenweider FX, Antonini A, Leenders KL, Mathys K. (1997a) Effects of high amphetamine doseson mood and cerebral glucose metabolism innormals using positron emission tomography(PET). [submitted] Psychiatry Research:Neuroimaging. Vollenweider FX, Antonini A, Leenders KL, Oye I, Hell D, Angst J. (1997b): DifferentialPsychopathology and patterns of cerebralglucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers measured byFDG-PET. Eur Neuropsychopharmacol 7:25-38 Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, Angst J.
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4. Why Study Hallucinogenic Drugs in Animals?
Mark A. Geyer, Ph.D What can we learn from studies of hallucinogenic neurotransmitter dopamine. Dopamine is the drugs in animals? The Church of Scientology has neurotransmitter that is believed to mediate the labelled such studies funded by the National Institute behavioral actions of drugs such as amphetamine and on Drug Abuse (NIDA) and the National Institute of cocaine. Despite the fact that very little evidence Mental Health (NIMH) as worthless wastes of the exists for a causal abnormality in dopamine systems taxpayers' money. This year, the Council for in the brains of schizophrenia patients, the vast Citizens Against Government Waste has joined in majority of these patients are treated currently with the fight against the Federal funding of such research, dopamine antagonists, that is, drugs that block the singling out a 25 year study of hallucinogen actions of dopamine. Many of these treatments are mechanisms in animals, supported by NIMH, as sufficiently successful to enable patients to live and being particularly wasteful. In years past, my often work in society rather than face a lifetime of research grant from NIDA supporting behavioral hospitalization, but they may not be the optimal studies of hallucinogens in rats has been targeted by treatments, are certainly not cures, and have proven animal rights activists, including a candle-light vigil ineffective in a large number of patients. Dopamine protesting a study of 102 rats given phencyclidine.
antagonists also produce unwanted side effects in the Nevertheless, I and many other scientists believe that form of serious Parkinsonian-like symptoms such as we can learn important information from basic studies muscle rigidity. of hallucinogen action in animal models and that this In the past decade, we have come to recognize information may lead to the alleviation of human that many of these patients who did not benefit from sufferring. The present essay will illustrate how such treatment with dopamine antagonists can be treated benefits may be realized. From the outset, it should effectively with another drug, clozapine, that is be acknowledged that there are many reasons one relatively weak as a dopamine antagonist but is also an antagonist at receptors for several other responsible for the fascinating and often profound neurotransmitters, including serotonin. Serotonin is effects of hallucinogens. Many believe that exploring the neurotransmitter that is believed to mediate the the effects of hallucinogens has the potential to teach psychological effects of both hallucinogens and us important lessons regarding the nature of entactogens. Clozapine has also proven to be consciousness and the way it relates to the brain.
remarkable in that it achieves its therapeutic effects in Here, the focus is specifically on the possible applications of such an understanding to the treatment Parkinsonian-like side-effects. It does, however, of mental illness, a more limited but still important produce potentially fatal blood abnormalities in perhaps 1% of patients and is, therefore, both riskyand costly. Given the devastating lifetime nature of schizophrenia, these risks and costs are often deemedacceptable by patients, families, and physicians, Some 40 years ago, the advent of antipsychotic largely because the clozapine treatment can be so remarkably effective. Thus, the key message is that schizophrenia led to a revolution in our mental health these treatment-resistant patients, who have failed to care system. Due in large part to the effectiveness of respond to any number of dopamine antagonists, can these medications in many patients, the longstanding be treated pharmacologically and can again lead practice of institutionalizing schizophrenia patients for relatively productive lives. Accordingly, the search their lifetime in state-run mental hospitals gradually has been intense to understand the therapeutic came to an end. Indeed, few of these state mental mechanism(s) of action of clozapine and to identify hospitals remain today. Nevertheless, these new drugs that would have similar therapeutic effects medications are not without unfortunate serious side- without the potentially fatal side-effects. One of the effects and are not effective in treating all candidates for such a drug is what could aptly be schizophrenia patients. Schizophrenia has long been called a hallucinogen antagonist that has been thought to include a group of disorders having identified directly by animal studies of hallucinogen different etiologies and requiring different treatments for different patients. Virtually all of our current arrayof antipsychotic drugs, however, work via a common Geyer, Hallucinogenic drugs in animals as the decrease in responding when the same Theories regarding the abnormalities responsible stimulus is presented repeatedly. For example, for the symptomatology of the group of disorders we habituation enables us to learn to ignore the repetitive schizophrenia have often suggested but unimportant ticking of a clock. The process of importance of deficits in early forms of filtering, habituation is essential to the selectivity of attention, gating, and information processing. Such theories since only by learning to ignore irrelevant stimuli posit that deficient gating of sensory and cognitive (i.e. habituate) can one focus attention specifically on information results in an overloading inundation of significant events. Another form of information information and consequent disorganization of processing is PPI, which is the normal suppression of thought processes (the hallmark of schizophrenia) the startle reflex when the intense startling stimulus (e.g. Braff and Geyer, 1990). In parallel, the actions is preceded by a weak prestimulus. In PPI, a weak of hallucinogens have often been related to changes in prepulse inhibits the behavioral response to a filtering mechanisms, e.g. the doors of perception powerful sensory stimulus. In all animals tested, PPI described by Aldous Huxley. Many investigators occurs when the prepulse and startling stimuli are in have suggested that an understanding of the the same or different sensory modalities. It does not mechanisms contributing to effects of these drugs appear to be a form of learning, since it occurs on the could provide insight into the abnormalities of brain first exposure to the prepulse and pulse stimuli, and function that lead to psychotic disorders. It is not it does not exhibit habituation over multiple tests.
necessary to argue that hallucinogens mimic all the PPI is considered to be an example of a pre-attentive and largely involuntary filtering mechanism because schizophrenia to believe that they affect some of the of the very short time interval between the prepulse same brain systems that can be disturbed in and the startle stimulus (i.e. 30-300 msec) that is psychiatric illnesses (Geyer and Markou, 1995).
sufficient to produce the inhibition. In contrast, Thus, an understanding of hallucinogen actions may habituation operates at much longer time frames and be relevant to specific aspects of schizophrenia rather involves the cognitive processing of the information than the entire complex syndrome. In recent years, content of the stimuli.
this idea of gating or filtering deficits in schizophreniahas been studied successfully using measures of Startle Habituation in Schizophrenia
startle responses. A number of experiments have In keeping with the theory that schizophrenia is used laboratory animals to explore the similarities characterized by an inability to inhibit responding to between the effects of so-called psychotomimetic unimportant events, the habituation of acoustic startle drugs and the abnormalities of information processing (startle elicited by bursts of noise presented through observed in patients with schizophrenia or related disorders. Our group has taken advantage of the schizophrenia (Geyer and Braff, 1982; Braff et al., opportunity for cross-species studies of information 1992). Relative to either normal controls or non- processing provided by startle response tests.
psychotic psychiatric patients, actively ill patients Specifically, two examples of fundamental filtering with schizophrenia were found to exhibit a slower rate mechanisms we have studied using the startle of habituation, that is, they continued to respond to response are habituation and prepulse inhibition the noises longer than the controls even though the noises had no particular meaning. It is important tonote that all three groups were similar in response to Startle Measures of Information Processing
the initial presentations of the startling noises. Thus, The startle reflex is a collection of responses to the deficit in habituation was seen in the absence of sudden intense stimuli that has provided a useful any change in startle reactivity, consistent with the approach to studying the neural control of simple notion that the abnormality involves the processing behaviors. One major advantage of startle response of information rather than basic sensory reactivity.
paradigms is that similar behavioral phenomena can Others have reported similar deficits in the be studied in a variety of species (Geyer and Markou, habituation of cutaneous startle (elicited by tiny 1995). In humans, the blink reflex component of the electric shocks) in psychotic patients, also in the startle response is measured using EMG. In small absence of differences in startle reactivity (Bolino et animals, a movement sensor is used to measure the al., 1994). The observation of deficits in both whole-body flinch elicited by startling stimuli. Of acoustic and cutaneous startle habituation indicates importance for the present work is not the reflex some generality in the phenomenon. Deficits in phenomenon itself, but two conceptually important habituation in schizophrenia patients do not simply forms of information processing - habituation and PPI result from medications or psychotic behavior per se, - that can be demonstrated using measures of startle.
since schizotypal patients who exhibit behavioral One is habituation, which is often considered to be abnormalities but are not receiving antipsychotic the simplest form of learning. Habituation is defined medications and are not grossly psychotic also show The Heffter Review of Psychedelic Research, Volume 1, 1998 habituation deficits (Cadenhead et al., 1993). If such hallucinogens as models of the parallel deficits in deficits in habituation can be generalized to other gating functions observed in schizophrenic and sensory input and response output systems, perhaps schizotypal patients. Furthermore, they support the even including thoughts to which most of us readily idea that the special therapeutic actions of the habituate, patients having such an abnormality would antipsychotic clozapine may be related to its be expected to have difficulties in organizing a serotonin-2 antagonist properties and that selective coherent view of the world - they would literally be unable to differentiate important from unimportant antagonists) might help at least some patients with events or direct their attention selectively to specific stimuli or thoughts.
The effects of "entactogens" on habituation in rats further implicate the serotonergic system in the Startle Habituation in Animals
control of startle habituation. These drugs, including Studies in rats have suggested that brain 3,4-methylenedioxy-N-methyl amphetamine (MDMA serotonergic systems, which are defined by the or "Ecstasy") and alpha-ethyltryptamine (AET or neurons that use serotonin as their neurotransmitter, "Love Pearls"), are potent releasers of serotonin from control startle habituation. These effects appear to be neurons in the brain and robustly impair the due to the activation specifically of one of the several habituation of startle responses (Kehne et al., 1992; subtypes of the brain's receptors for serotonin, the Martinez and Geyer, 1997). The anti-habituation serotonin-2 receptor. The effects of hallucinogens are effects of serotonin releasers are prevented by believed to be due largely to their actions as pretreatment with serotonin reuptake inhibitors, such serotonin-2 agonists, that is, they mimic the effects of as fluoxetine ("Prozac"), which prevent the drug- serotonin at these particular receptors. Hallucinogens induced release of serotonin from serotonergic (but have often been suggested to enhance one's ability to not dopaminergic) neurons (Kehne et al., 1992; see familiar things as novel and to increase the Martinez and Geyer, 1997). Thus, it appears that perceptual impact of both external events and internal these entactogens impair habituation by releasing thoughts. While such an experience may be desirable serotonin, which then presumably acts upon in one who knows that the distortion of information processing is due to the ingestion of a drug and is The psychotomimetic agent phencyclidine (PCP) time-limited, it must be quite a different experience to also impairs the habituation of startle responding in recognize that this condition reflects the permanent rats, especially at relatively low doses (Geyer et al., status of one's brain. In animals, of course, we study 1984). Thus, impairments of startle habituation effects of these drugs in the absence of insight about appear to constitute a behavioral effect in rats that is the source of the perceived abnormality - rather like common to hallucinogenic serotonin agonists, studies of LSD in which the drug was given to entactogenic serotonin releasers, or psychotomimetic subjects without their knowledge. Relatively early PCP-like drugs.
studies demonstrated that the hallucinogens LSD andmescaline impaired the habituation of tactile startle Prepulse Inhibition in Schizophrenia
(elicited by small puffs of air) in rats (Geyer et al., Prepulse inhibition of acoustic startle is deficient 1978; Geyer and Tapson 1988). Similarly, Davis et in schizophrenia patients (Braff et al., 1978).
al. (1986) demonstrated robust increases in acoustic Theoretically, such a deficit in a fundamental form of startle in rats treated with mescaline that were not pre-attentive filtering may distort information and associated with any change in the initial level of produce a form of sensory overload which may lead to startle reactivity and appeared to be attributable to a the disorganized thought processes that are the specific effect on the habituation of startle. In hallmark symptoms of schizophrenia. This deficit in contrast, amphetamine increased startle on all trials, PPI has been confirmed in studies of medicated, but reflecting a more generalized increase in startle still-ill patients with schizophrenia in various reactivity (Davis et al., 1986). This study was countries and by investigators using different methods among the first to implicate serotonin-2 receptors in (Bolino et al., 1994; Braff et al., 1992; Grillon et al., startle habituation, as the effect of mescaline, but not 1992). As with habituation, that of amphetamine, was abolished by pretreatment schizotypal patients (Cadenhead et al., 1993). Furthermore, there is some Subsequent studies with a variety of serotonin-2 evidence that PPI deficits in schizophrenia may be antagonists demonstrated that the antagonists by reversed by successful treatment with antipsychotic themselves could accelerate tactile startle habituation drugs (Hamm et al., 1995; Weike et al., 1996).
(Geyer and Tapson, 1988). Thus, the opposite effects Only recently have studies attempted to relate these of hallucinogenic serotonin-2 agonists and serotonin- observed deficits in sensorimotor gating functions to 2 antagonists in the modulation of startle habituation measures of thought disorder. Perry and Braff (1994) provide strong support for the use of these have reported a significant correlation within a group Geyer, Hallucinogenic drugs in animals of schizophrenia patients between deficits in PPI and by releasing serotonin which, in turn, acts upon thought disorder as assessed by psychological tests.
Further studies in this vein will be important in In rats, PPI is reduced dose-dependently by the relating the abnormalities in basic forms of administration of the psychotomimetic PCP or information processing, such as PPI or habituation, related drugs such as ketamine (Mansbach and Geyer to more complex symptoms, treatment outcomes, or 1989, 1991). Importantly, the effects of PCP are quality of life.
Prepulse Inhibition in Animals
antipsychotics including clozapine (Bakshi et al., In rats, hallucinogenic serotonin agonists have 1994; Geyer et al., 1990). Thus, the PCP-disruption been found to disrupt PPI, mimicking the deficit in of PPI may be a useful model for identifying novel PPI observed in schizophrenia patients. LSD, which atypical antipsychotic treatments. In humans, this mimics the effects of serotonin (i.e. has agonist class of drugs produces symptoms that mimic some effects) at multiple serotonin receptors, dose- features of schizophrenia (Javitt and Zukin, 1991).
dependently reduces PPI Specifically, PCP-induced clinical effects have been Similarly, PPI is reduced by hallucinogens that have linked to the characteristics and pathophysiology of more selective agonist effects at serotonin-2 receptors, the "deficit" symptoms of schizophrenia that are the such as 2,5-dimethoxy-4-iodoamphetamine (DOI).
most difficult to treat with the typical antipsychotics that work via dopamine antagonism. Furthermore, hallucinogenic serotonin-2 receptor agonists are ketamine has been shown to produce a schizophrenia- blocked by pretreatment with serotonin-2 antagonists like deficit in PPI in normal control subjects (Karper including MDL 100907 (Padich et al., 1996; Sipes et al., 1994), induce psychotic symptoms in normal and Geyer, 1994, 1995), but not by the dopamine volunteers (Malhotra et al., 1996), and exacerbate antagonist and traditional antipsychotic haloperidol psychotic symptoms in schizophrenia patients (Lahti (Padich et al., 1996). Such findings have contributed et al., 1995), providing some validation of the to the current investigation of MDL 100907 as a similar animal studies.
possible non-dopaminergic antipsychotic in patientswith schizophrenia. Because MDL 100907 is devoid of dopamine antagonist properties, it will not produce The study of gating or filtering deficits in the Parkinsonian-like side-effects that plague the schizophrenia and parallel animal models based on current class of antipsychotics. This drug is currently startle measures of information processing has (1997) being tested in clinical trials; early reports demonstrated considerable utility in the exploration from these trials have been promising. If it does prove to be antipsychotic, it will represent one of the schizophrenia in general and the drug-induced models very few novel treatments used to treat schizophrenia of psychosis in particular. In rats, hallucinogens, that is not based on any dopamine antagonist effects.
entactogens, and PCP-like drugs mimic both the Thus, it may be particularly effective in the subgroup impairments of habituation and disruptions in PPI of schizophrenia patients for whom dopamine observed in patients with schizophrenia. Either of antagonists are ineffective. Clearly, if this promise is these abnormalities could be responsible for the realized, it will be a direct benefit of animal studies thought disorder that is central to the symptoms of on the mechanisms responsible for the effects of schizophrenia. The effects of hallucinogens and entactogens on both habituation and PPI have been PPI in rats is also reduced by systemic treatment related to their particular mechanisms of action within with serotonin releasers, or "entactogens", including serotonergic systems. These observations in rats have led directly to the development of serotonin-2 (MDEA or "Eve"), fenfluramine, and AET (Kehne et antagonists for the treatment of schizophrenia. The al., 1992, 1996; Mansbach et al., 1989; Martinez and effects of PCP and related psychotomimetics in rats Geyer, 1997). The PPI-disruptive effects of serotonin appear to be sensitive specifically to atypical releasers are prevented by pretreatment with the antipsychotics and may aid in the identification of serotonin reuptake inhibitor fluoxetine, which novel antipsychotic therapeutics. By virtue of the prevents the drug-induced release of serotonin from extensive knowledge regarding the neurobiological serotonin neurons while having little effect by itself.
substrates involved in the modulation of such gating As with the classical hallucinogens, the serotonin-2 functions as habituation and PPI in laboratory animals, the further application of these measures may antipsychotic is also effective in blocking the effects of enable the elucidation of both the mechanisms of serotonin releasers on PPI (Padich et al., 1996).
action of psychotomimetics in humans and their Thus, it appears that these entactogens disrupt PPI possible relevance to the abnormalities that lead toschizophrenia and related psychotic disorders.
The Heffter Review of Psychedelic Research, Volume 1, 1998 Shortly after the discovery of the neurotransmitter Bolino F, Di Michele V, Di Cicco L, Manna V, serotonin, it was suggested that LSD might owe its Daneluzzo E, Cassachia M. Sensorimotor gating profound effects to actions on serotonin systems in and habituation evoked by electrocutaneous the brain, due to structural similarities between LSD stimulation in schizophrenia. Biol Psychiat 36: and serotonin. It was also suggested that we might 670-679, 1994.
learn something about the causes and/or treatment of Braff DL, Geyer MA. Sensorimotor gating and psychotic disorders by discovering the mechanisms of schizophrenia: Human and animal model studies.
action of LSD and related hallucinogens. While Arch Gen Psychiatry 47:181-188, 1990.
European psychiatrists have continued to explore this Braff DL, Grillon C, Geyer M. Gating and possibility (Hermle et al., 1993), most American habituation of the startle reflex in schizophrenic psychiatrists dismissed the idea some 30 years ago patients. Arch Gen Psychiat 49: 206-215, 1992.
because of largely specious arguments (Geyer and Braff D, Stone C, Callaway E, Geyer M, Glick I, Markou, 1995). In retrospect, one can argue that the Bali L. Prestimulus effects on human startle effectiveness of a serotonin-2 antagonist such as MDL Psychophysiology 15: 339-343, 1978.
100907 in the treatment of schizophrenia could and Cadenhead KS, Geyer MA, Braff DL. Impaired startle would have been explored long ago if animal studies of hallucinogens had been supported more widely.
schizotypal patients. Am J Psychiat 150: 1862- Instead, progress has been slow, being based on the work of relatively few laboratories. For many years, Davis M, Cassella JV, Wrean WH, Kehne JH.
it was thought that LSD functioned as a serotonin Serotonin receptor subtype agonists: Differential antagonist and that serotonin acted as a tranquilizing effects on sensorimotor reactivity measured with neurotransmitter in opposition to the activations acoustic startle. Psychopharmacol Bull 22:837- associated with the neurotransmitter dopamine.
Subsequent studies in animals revealed that LSD and Geyer MA, Peterson L, Rose G, Horwitt D, Light R, related compounds actually act as serotonin agonists, Adams L, Zook J, Hawkins R, Mandell AJ.
that is, they mimic some actions of serotonin (at the hallucinogens on sensory integrative function: Although entrenched ideas fade slowly, informed Tactile startle. J Pharmacol Exp Ther 207:837- neuroscientists are now recognizing that serotonin Geyer MA, Braff DL. Habituation of the blink reflex neurotransmitter systems and often work in concert.
Hence, it is now acknowledged that both serotonin Psychophysiol 19:1-6, 1982.
Geyer MA, Segal DS, Greenberg BD. Increased contribute importantly to the treatment of psychosis.
This new insight, with its practical consequence phencyclidine. Neurobehav Toxicol Teratol being the current testing of a hallucinogen antagonist 6:161-164, 1984.
in schizophrenia patients, has evolved directly from Geyer MA, Tapson GS. Habituation of tactile startle multidisciplinary studies of laboratory animals.
is altered by drugs acting on serotonin-2 These animal studies may not have been motivated receptors. Neuropsychopharmacol 1:135-147, explicitly by the possible discovery of new treatments for any disease; most were designed simply to further Geyer MA, Swerdlow NR, Mansbach RS, Braff DL.
our basic knowledge of serotonin systems and the Startle response models of sensorimotor gating mechanisms of action of hallucinogenic drugs.
and habituation deficits in schizophrenia. Brain Without such basic knowledge, however, one can be Res Bull 25: 485-498, 1990.
confident that biomedical science will not advance Geyer MA, Markou A. Animal models of psychiatric and new treatments for psychiatric disorders will not disorders. In: Psychopharmacology: The be developed. Thus, despite the fact that such Fourth Generation of Progress (FE Bloom and research is subject to ridicule by those who would DJ Kupfer, eds), Raven Press, Ltd, New York, stop animal research, I contend that animal studies of pp. 787-798, 1995.
hallucinogen mechanisms have the potential to Geyer MA. Behavioral studies of hallucinogenic alleviate human sufferring.
drugs in animals: Implications for schizophreniaresearch. Pharmacopsychiatry, in press.
Grillon C, Ameli R, Charney DS, Krystal J, Braff Bakshi VP, Swerdlow NR, Geyer MA. Clozapine DL. Startle gating deficits occur across prepulse antagonizes phencyclidine-induced deficits in intensities in schizophrenic patients. Biol sensorimotor gating of the startle response. J Psychiat 32: 939-943, 1992.
Pharmacol Exp Ther 271: 787-794, 1994.
Geyer, Hallucinogenic drugs in animals Hamm A, Weike A, Bauer U, Vaitl D, Gallhofer B.
Padich RA, McCloskey TC, Kehne JH. 5-HT modulation of auditory and visual sensorimotor unmedicated schizophrenics. Psychophysiology, gating: II. Effects of the serotonin-2A antagonist 33 (Suppl 1): S65, 1995.
MDL 100,907 on disruption of sound and light Hermle L, Funfgeld M, Oepen G, Botsch H, prepulse inhibition produced by 5-HT agonists Borchard D, Gouzoulis E, Fehrenbach RA, in Wistar rats. Psychopharmacology 124: 107- Mescaline-induced pathological, neuropsychological, and neuro- Perry W, Braff DL. Information-processing deficits and thought disorder in schizophrenia. Amer J Experimental psychosis as a tool for psychiatric Psychiat 151: 363-367, 1994.
research. Biol Psychiat 32:976-991.
Sipes TA, Geyer MA. Multiple serotonin receptor Javitt DC, Zukin SR. Recent advances in the subtypes modulate prepulse inhibition of the phencyclidine model of schizophrenia. Am J startle response in rats. Neuropsychopharm 33: Psychiat 148: 1301-1308, 1991.
Karper LP, Grillon C, Charney DS, Krystal JH. The Sipes TE, Geyer MA. DOI disruption of prepulse effect of ketamine on pre-pulse inhibition and inhibition of startle in the rat is mediated by attention. Abstr ACNP, 124, 1994.
serotonin-2A and not by serotonin-2C receptors.
Kehne JH, McCloskey TC, Taylor VL, Black CK, Behav Pharmacol 6:839-842, 1995.
Fadayel GM, Schmidt CT. Effects of serotonin Weike A, Globisch J, Hamm A, Bauer U. Prepulse releasers 3,4 Methylenedioxymethamphetamine inhibition and habituation of skin conductance (MDMA), 4-chloroamphetamine (PCA) and responses in schizophrenics: Neuroleptic drug fenfluramine on acoustic and tactile startle effects. Psychophysiol 33 (Suppl 1): S88, 1996.
reflexes in rat. J Pharmacol Exp Ther 260: 78-89, 1992.
Kehne JH, Padich RA, McCloskey TC, Taylor VL, Schmidt CJ. 5-HT modulation of auditory andvisual sensorimotor gating: I. Effects of 5-HTreleasers on sound and light prepulse inhibitionin Wistar rats. Psychopharmacology 124: 95-106, 1996.
Lahti AC, Koffel B, LaPorte D, Tamminga CA.
Subanesthetic doses of ketamine stimulatepsychosis Neuropsychopharmacol 13: 9-19, 1995.
Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, Breier A. NMDA receptorfunction and human cognition: the effects ofketamine Neuropsychopharmacol 14: 301-307, 1996.
Mansbach RS, Braff DL, Geyer MA: Prepulse inhibition of the acoustic startle response isdisrupted amphetamine (MDEA) in the rat. Eur JPharmacol 167: 49-55, 1989.
Mansbach RS, Geyer MA. Effects of phencyclidine and phencyclidine biologs on sensorimotorgating in the rat. Neuropsychopharm, 2: 299-308, 1989.
Mansbach RS, Geyer MA. Parametric determinants in pre-stimulus modification of acoustic startle:interaction with ketamine. Psychopharm 105:162-168, 1991.
Martinez DL, Geyer MA. Characterization of the habituation of startle 5. The Medicinal Chemistry of Phenethylamine Psychedelics
David E. Nichols, Ph.D.
I am sometimes asked, "how would you describe distinction between these two positions. On the one your research?" After many years my standard hand, we can design and study molecules in model response has evolved to, "I design molecular probes systems that allow us to predict that the structure of brain function." While the readers of this essay will have psychedelic activity, but on the other we may know that I have worked with psychedelics for absolutely cannot know the full nearly thirty years, my laboratory also is studying the psychopharmacological complexity of their effects in development of potential new treatments for the absence of clinical studies.
depression, as well as carrying out significant efforts Discussions of psychedelics as chemical to create new therapies for end-stage Parkinson's molecules, interacting with brain receptors, also disease. In each case, we are using relatively small tends to "demystify" psychedelics for those who view chemical molecules to interact with various brain them as sacraments. It is not my mission to gore targets to gain information that may enhance our anyone's sacred cow. In the realm of psychedelics, understanding of the underlying importance of those hard core science will say that these substances targets to normal brain function. In the latter two simply activate certain parts of the brain that examples, it is clear what the end point should be.
produce effects that might be predictable, if only we We should find better and faster ways to treat had a complete understanding of the brain and its depression, and we should find new drugs to restore neurobiology. At the other end of the spectrum are function to Parkinson patients who presently have no sincere people who believe that psychedelics are further hope. While the molecules we design often sacred substances, that can produce genuine nirvana, start out as experimental probes, if we have union with the cosmos, and the like--ecstatic states understood well the nature of our target, these that they believe have very little to do with brain structures may eventually become therapeutic anatomy or chemistry. These are the folks who talk about a new paradigm of mind, quantum What about probes of the brain receptors for consciousness, and the like. I do not plan to enter hallucinogens? What is the end point there, and this debate, but rather only to present a how is it relevant? There is one line of reasoning fundamentally reductionistic view of how these that says these peculiar substances can only be substances are now believed to interact with the assayed in man, and that any other approach is physical brain. My objective in this essay is to inherently invalid. While off the record one may provide some basic information about the medicinal occasionally be forced to admit to the essential core chemistry of psychedelic agents.
truth of this premise, it does not necessarily follow At its heart, medicinal chemistry (what I do) that any other type of research is completely and attempts to draw clear and meaningful relationships utterly useless. Readers will find further between the molecular features of a chemical confirmation of this fact in the chapter in this structure and the biological events subsequent to its volume by Dr. Mark Geyer. I have occasionally been administration to a living organism. Inherent in this challenged that the structure-activity studies I carry approach is the assumption that a relationship exists out have no relevance to the real world; that studies between chemical structure and biological effect. In in rats have no meaning. I do not believe this to be the context of psychedelic agents a relationship the case, and I shall explain why. We can very well certainly exists. It is in clearly and explicitly use receptor assays, and models employing trained defining this relationship that problems may arise.
laboratory animals (mostly rats) to tell us whether a Perhaps it would be helpful here to employ a new molecule may have the essential molecular crude analogy. One can clearly see that a features that would ultimately allow it to be relationship exists between gasoline and automobile classified as a psychedelic, were it to be tested in travel. What one cannot predict is whether a man. What we cannot do with animals, or with any particular tank of gasoline is destined to propel a car other nonhuman models, is to predict whether a toward Canada, Mexico, the Northeast, etc. The particular molecule will open the gates of heaven or outcome is dependent on the whims of the owner of stoke up the fires of hell. We must maintain a clear the vehicle. Similarly, one can predict that Nichols, Medicinal chemistry of phenethylamines psychoactive substances such as LSD will move the targets for any additional neurotransmitter that psyche from what has been called consensus reality, might be released (or any additional LSD molecules to some altered state of consciousness. What cannot that may happen to arrive). This is the reason that be predicted is the nature of that change or the LSD loses its effects when taken too often. The "direction" the altered state will take. It is an number of receptors for it just rapidly decreases! erroneous assumption to believe that medicinal What my research has done is to focus on key chemistry can design in elements of molecular sites in the brain, and attempt to identify the structure that will lead the psyche in a particular recognition elements that are necessary to bind to direction. The state of the art in medicinal chemistry and activate them. This was a goal when I started is not so advanced! This would be akin to assuming research in this field in 1969, and it remains that a particular blend of gasoline could somehow unattained in 1997. But, I think we are getting determine the direction that the car will be driven.
closer to understanding. To begin with, until a few What I am leading up to is the fact that there are years ago no one really had a good idea of what a key recognition elements within the structures of all receptor might look like. Today, we know that the psychedelic molecules that lead to their activity; vast majority of neurotransmitter receptors are phenethylamines have them, tryptamines have them, bundles of protein helices embedded in and spanning and LSD and other related ergolines have them.
the neuronal cell membrane. The receptor, Essential chemical features of these molecular therefore, can act as a "conduit" to allow information recognition elements activate a key brain target.
to pass through the neuronal membrane.
This activation then "enables" the brain to shift its One of the stable forms that proteins can adopt processing from ordinary waking consciousness and is called an alpha helix. This is somewhat the shape enter into whatever state is produced by all of a Slinky toy, or the shape of the threads around a psychedelic drugs. Most scientists now believe the bolt. It is now widely believed that most of the target, or "switch" for psychedelic molecules is a site serotonin receptors exist as a bundle of seven such known as the serotonin 5-HT2A receptor (Nichols alpha helices inserted into the neuron membrane.
1997). Just as turning on the power switch of a These seven helices are connected both on the television enables the TV to display images, but is outside and on the inside of the neuron membrane not responsible for what is seen, psychedelic with continuing loops of proteins, so that the whole molecules, by activating this brain receptor, "turn receptor, if it could be unwound and stretched out, on" some other set of amplifiers and processors that would simply be one very long chain of amino acids, allow nonordinary feelings and states of the basic building blocks of all proteins. A consciousness to occur.
schematic view of this type of receptor is presented While this may sound reductionistic to many in figure 1.
readers, it may also be useful to envisage an analogybetween this receptor and an automobile's ignition system, that must be switched on with a key beforethe car may go in any direction. It is up to themotivations of the driver, the power of the engine,the condition of the roads, etc. (i.e. the "set" and the"setting") to determine where and when the journeywill actually begin and end.
It is believed that during ordinary circumstances the brain 5-HT2A receptor is not highly activated.
That is, the daily ebb and flow of serotonin molecules does not produce an LSD-like state in usbecause not many serotonin molecules are releasedby neurons onto these receptors. When a psychedelic molecule enters the brain however, it binds verytightly to these receptors, producing an extensive and Figure 1. A schematic representation of a
prolonged activation state. In fact, the brain is so membrane-bound G-protein coupled receptor, of sensitive to activation of these receptors that when which the serotonin 5-HT2A receptor is an example. they are overstimulated, as for example when one The receptor consists of 7 alpha helices, represented ingests a psychedelic such as LSD, they quickly here by tubes, connected on the inside and outside decline in density so as to reduce the numbers of with continuing loops of protein. The Heffter Review of Psychedelic Research, Volume 1, 1998 The process of neurotransmission involves the The assumption in my laboratory has been that release of neurotransmitter molecules from the all the various types of psychedelic agents, at a terminal of a neuron. These diffuse through the minimum, interact with brain serotonin 5-HT2A solution in the space between the two neurons (called receptors in this way, and what we have tried to do is the synapse), and are attracted to the receptor, to understand how the chemical features of these probably due to electrostatic fields generated by the molecules lead to their binding to this receptor. We charges on the amino acids in the receptor and shall now move on to a more chemical discussion of charges on the neurotransmitter. The neuro- what properties are possessed by the molecules transmitter molecule fits into the ligand recognition themselves, that may allow them to activate domain of the receptor, where a series of events is then initiated. It is believed that when the neuro- Following more than two decades of work, in transmitter "docks" into the receptor, the seven several laboratories, there are now some ideas about alpha helices rearrange the way they are oriented what is required for activity, at least in some classes with respect to each other. That is, they twist, turn, of molecules. For example, as a crude and bend, undergoing what is called a representation, figure 2 shows some of the structural "conformational change," in order to achieve a new features that may be important within the packing arrangement that is compatible with the phenethylamine type hallucinogens for receptor presence of the neurotransmitter in their midst. This recognition and activation (Monte et al. 1996). First is a reasonable hypothesis, and could be explained in of all, the cyclic hexagonal ring in the center of the a very technical way if time and space permitted.
figure is called a phenyl ring. The letter N in the What is not adequately represented in figure 1 is NH3 to the right of that represents the nitrogen atom.
the relatively large piece of receptor protein that is The lines connecting the two represent two carbon used to connect the seven alpha helices on the inside atoms attached together, called an ethyl group.
of the receptor. These protein chains, particularly a Hence, these molecules, in general, are called large loop that connects helices 5 and 6, as well as phenethylamines or sometimes phenylethylamines: a the end of the protein chain that follows helix 7 on phenyl ring separated by an ethyl grouping from an the inside of the receptor, adopt a shape that allows them to bind to another type of protein, called aGTP-binding protein (G protein for short). When H-bond donor
the neurotransmitter molecule binds to itsrecognition domain in part of the receptor on the outside of the membrane, it causes changes in the (asp on TM3)
shape of the receptor, and the movement of the receptor helices then apparently causes large shape Region of
changes in the loops and chains on the part of the Hydrophobic
receptor that is inside of the neuron. When this Region of Steric
occurs, the G proteins dissociate from the receptor because the fit between them is no longer complementary, they bind to molecules of GTP in H-bond donor
the cytoplasm, and then initiate a series ofbiochemical changes in the neuron that constitutesthe actual "message" of the neurotransmitter; Figure 2. A schematic representation of a
calcium levels in the neuron change, certain proteins phenethylamine hallucinogen similar to DOB are activated that attach phosphate groups to other interacting with the ligand binding domain of the proteins, etc. The whole process is a complex serotonin 5-HT2A receptor. Important sites for sequence of events known as a signaling cascade.
chemical interaction include the amino group, the All these biochemical changes produced in the two oxygen atoms, the hydrophobic "X" group, and interior alter the state of the neuron, making it more the central phenyl ring itself. Taken from Monte et or less easy to send a signal itself. Ultimately, at least for psychedelics, these changes in brainbiochemistry somehow lead to an alteration in The nitrogen atom has the property of being consciousness. How this occurs will remain a basic, in the context of acid-base chemical reactions.
mystery for many years to come, if we can ever Ammonia is a common household base. Bases are neutralized by chemical reaction with acids.
Nichols, Medicinal chemistry of phenethylamines Common household acids are vinegar and soft top and bottom of the structure, as the letter O, with drinks. Since acids neutralize bases, in the body the the dashed lines toward the Hs. These oxygen atoms basic amino group of the phenethylamines is also are essential to binding and activation of the "neutralized" by reacting with weak acids. This receptor. Alexander Shulgin carried out a number of means that the basic amino group, which is normally studies where he replaced these oxygen atoms with represented by an NH2, has added an extra hydrogen other atoms such as sulfur, and in each case the atom, or proton (i.e. the acid), and now is an NH + activity was greatly reduced or lost completely. In the plus sign denoting that the hydrogen atom the simplest compounds, these oxygen atoms are not brought a positive charge with it to the molecule.
part of a ring system, as shown here, but rather are This positive charge is believed to lead to an freely swinging. They are hooked to the phenyl ring, attraction for an amino acid in the serotonin receptor and then another carbon atom called a methyl group called an aspartic acid residue. This key aspartic is attached. This grouping looks like this: -OCH3.
acid residue is located on one of the membrane- Because of the numbering system for the locations spanning alpha helices designated as transmembrane around the phenyl ring, these methoxy groups are helix 3. This amino acid is a weak acid, similar in attached at positions numbered 2 and 5. The "X" acidity to vinegar, but it too has lost it's hydrogen group is attached at the position numbered 4. Thus, atom by neutralization in the body. The these compounds are often called 2,5-dimethoxy-4- characteristic feature of weak organic acids is the presence of a COOH grouping of atoms. Since In figure 2, however, both oxygen atoms are molecules prefer to be neutral, and not carry a shown incorporated into pentagonal rings (known as charge on them, the departure of it's hydrogen atom dihydrofurans), that have common edges with the with a positive charge left behind a corresponding central phenyl ring (i.e. they are "fused" to the negative charge. Thus, the aspartic acid is shown phenyl ring). This has the effect of "locking" the not as a -COOH, but rather as a -COO-, indicating oxygen atoms so they cannot undergo rotational that the hydrogen atom is gone, and that a negative movement. Experiments in my laboratory have charge was left behind. It is the attraction between shown that this gives the most active orientation of the amino group, with the positive charge, and the the oxygen atoms in producing hallucinogenic aspartic acid residue, with the negative charge, that effects. We believe that the oxygen atoms interact is believed to be one of the most powerful forces in with the receptor through hydrogen bonds, causing a neurotransmitter to bind to its receptor.
represented as the dashed lines connecting the This attraction is denoted by the series of short oxygen atom to a hydrogen atom (denoted by the vertical lines between the NH + 3 and the -OOC- in the letter H) arising from a hydrogen bond donating site figure. As a crude analogy, one can appreciate the in the receptor. Because oxygen atoms have extra force that occurs between the two poles of a magnet.
electrons in their outer shell, and certain types of On the left side of the phenethylamine molecule, hydrogen atoms attached to oxygen or nitrogen a large "X" is pictured above an elliptical area atoms have a slight "deficiency" of electrons, there is labeled as a "Region of Hydrophobic Interaction." a fairly strong attraction between them that is called Hydro is a prefix denoting water, and phobic comes a hydrogen bond.
from the same root as phobia, or fear of something.
Finally, there is also a small area shown in Thus, hydrophobic is a term meaning that something figure 2 labeled "Region of Steric Occlusion." In the is "water-hating." Not surprisingly, therefore, phenethylamines, there is only a hydrogen atom (H) hydrophobic molecules typically have an oily or at the end of the dashed line in this region. These greasy texture. This is an important place in the are representatives of compounds that Shulgin has receptor that seems to prefer to bind to atoms or named 2C compounds (e.g. 2C-B, 2C-T, etc.). The groups that have an oily, non-water soluble nature.
2C represents the fact that there are only two carbons Extremely potent phenethylamine hallucinogens between the phenyl ring and the amine. However, if have atoms attached at this position such as bromine, a third carbon atom is attached, that is, a -CH3 group iodine, or sulfur. Indeed, if the rest of the structure is attached at the end of the dashed line that is lying is completely identical, the changing of what is over the region of steric occlusion, these compounds attached only at this location of the phenyl ring can are typically called amphetamines. This carbon in give compounds that begin to approach the potency the ethyl group is called the alpha position because it of LSD on a dosage basis! is the first carbon atom attached to the amine Another important feature of these compounds nitrogen. (The second carbon atom from the amine, is the two oxygen atoms. These are shown near the next to the phenyl ring, is called the beta position.) The Heffter Review of Psychedelic Research, Volume 1, 1998 Nothing larger than a single carbon atom with its Figure 3. Rigidification of the methoxy groups in
attached hydrogens, called a methyl group, can be DOB leads to compounds with increased activity attached here. In organic chemistry, the word steric while a similar transformation in mescaline leads to is used to refer to the size or bulk of a portion of the molecule. We have therefore designated this portionof the receptor as an area that cannot tolerate steric While it has generally been assumed that bulk. In other words, it is a region of steric mescaline activates the same receptors as all of the other types of psychedelics, there are clearly some So, the molecule binds through a combination of important differences when one actually looks at the forces, to the amino group, the two oxygen atoms, molecular architecture of mescaline compared with and the hydrophobic "X" group, and in addition, the DOB-like molecules. This is an issue that continues receptor has many hydrophobic amino acid groups to perplex us, and will be the focus of additional within the ligand binding domain that simply studies as we attempt to identify the active shape of embrace the phenyl ring and the ethyl group which mescaline-like molecules when they bind to the themselves are hydrophobic. The molecule just becomes as snug as a bug in a rug! In the process of These might appear, at first glance, to be easy being attracted to, and wrapping around the questions to solve, but in fact the design of molecular psychedelic molecule, the receptor changes and probes to study this question is quite problematic.
moves itself, and sets off the sequence of biochemical When a change is made in the structure of a events described earlier.
molecule, many variables are changed simul- The same thing cannot be said for molecules taneously and one often cannot know which one was related to mescaline, however. We recently (Monte responsible for the observed effect. For example, in et al. 1997) showed that carrying out the same types figure 3, incorporation of the methoxy groups into of chemical modifications that led to high activity in the pentagonal furan rings does not simply "lock" the DOB type compounds, gave molecules that the orientation of the oxygen atom. It also appear inactive in our animal models when applied introduces new pieces of molecular ‘baggage.' That to mescaline. Illustrated in figure 3 below are the is, a methoxy group is -OCH3, while the relevant examples. Locking the methoxy groups of corresponding part of the furan ring structure is DOB into rings (as also shown earlier in the -OCH2CH2-. Furthermore, in mescaline, the "receptor" model) gives an increase in potency. On positions in the phenyl ring (the hexagonal central the other hand, locking the distal methoxy groups of ring) that are adjacent to the ethylamine chain are mescaline into rings in the same way led to inactive occupied only by hydrogen atoms, while in the rigid analogue on the right, they serve as the anchorpoints for the cyclic ring structures. In the usual circumstance, one cannot know what effect these additional modifications have on overall activity.
Our analogy to the DOB molecule however, suggeststhat incorporation of the oxygen atoms into these ring structures should not affect activity, if the oxygen atom in the methoxy group possesses thesame orientation as in the ring structure upon binding to the receptor. Our extension of thisapproach to mescaline, leading to inactivecompounds, suggests therefore that the oxygen atomsof mescaline do not adopt the orientation of the rigid analog shown on the right, and that perhaps the methoxy groups of mescaline may rotate into somedifferent, and as yet undefined orientation. What is this orientation? That is a question we will attempt to address in future studies.
Nichols, Medicinal chemistry of phenethylamines What's next?
The missing piece(s) of the puzzle are now the links between these biochemical events, and the Nichols, D.E., Snyder, S.E., Oberlender, R. Johnson, parts of the brain that must be involved in changing M. and Huang, X. (1991) 2,3- Dihydrobenzo- consciousness. It will probably be a long time before furan Analogues of Hallucinogenic Phenethyl- this connection can be made. In the meantime, amines, J. Med. Chem., 34, 276-281.
however, there are a number of scientifically valid Monte, A.P. Marona-Lewicka, D. Cozzi, N.V.
approaches that will give useful information.
Nelson, D.L. and Nichols, D.E. (1995) Recently, for example, we have "stumbled" upon a Conformationally restricted tetrahydro-1-benz- simple phenethylamine molecule that has affinity for oxepin analogs of hallucinogenic phenethyl- the 5-HT2A receptor nearly 100-fold higher than any amines, Medicinal Chemistry Research., 5, 651-
other compound discovered to date, including LSD itself! There is no particular reason to search for Monte, A.P. Marona-Lewicka, D. Parker, M.
more potent compounds, but often such molecules Wainscott, B. Nelson, D.L. and Nichols, D.E.
prove to be quite useful as research tools. For (1996) Dihydrobenzofuran analogues of hallu- example, when a molecule has very high affinity for cinogens. 3. Models of 4-Substituted (2,5-di- a receptor, it is often possible to introduce methoxyphenyl)alkylamine derivatives with radioactive atoms into the molecule that allow one to rigidified methoxy groups, J. Med. Chem., 39,
visualize sites where the molecule binds in the brain.
This has already been done with molecules such as Monte, A.P. Waldman, S.R. Marona-Lewicka, D.
DOB, DOI, and LSD. However, a molecule with Wainscott, D.B. Nelson, D.L. Sanders-Bush, E.
even higher affinity can be used at lower and Nichols, D.E. (1997) Dihydrobenzofuran concentrations and dosages to detect and visualize analogues of hallucinogens. 4. Mescaline receptors. This new molecule, with exceedingly Derivatives," J. Med. Chem., 40, 2997-3008.
high affinity for the 5-HT2 class of receptors will no Nichols, D.E. (1997) Role of Serotonergic Neurons doubt be useful to label and visualize these receptors and 5-HT Receptors in the Action of in the brain. Indeed, we have already begun Hallucinogens," in Handbook of Experimental discussions with a firm that supplies radioactive Pharmacology. Serotoninergic Neurons and 5- molecules to prepare radioactive forms of this HT Receptors in the CNS, H.G. Baumgarten and molecule for evaluation.
M. Göthert, Eds., Springer-Verlag GmbH & Literature reports now also suggest that a Co., Heidelberg, Germany, pp 563-585.
tentative 3-dimensional structure for the family of G-protein coupled receptors may not be far off. This isthe receptor family to which nearly all of theserotonin receptors belong. Perhaps within the nextyear or two a good structure may become available.
With that event, we would begin computer modelingstudies to dock our molecules into this receptorstructure in attempts to gain an appreciation ofwhich structural features of the molecule arenecessary for binding and activation of the receptor.
If this can be accomplished, we should also be ableto design new molecules to test hypotheses aboutwhich molecular features are necessary for receptorbinding. That would be a very exciting developmentbecause it would be the first time that it mightbecome possible to design a molecule, de novo, to fita particular receptor. Clearly, if we can retain ourresearch funding, the most exciting developments inthe medicinal chemistry of psychedelic agents are yetto come.
6. Are The "Entactogens" a Distinct Psychoactive Substance Class?
The Contribution of Human Experimental Studies to the Classification of MDMA and
Other Chemically Related Methylenedioxyamphetamine Derivatives
Euphrosyne Gouzoulis-Mayfrank, M.D. and Leo Hermle, M.D.
reported (Greer and Tolbert 1986). This psychotropic profile makes MDMA, in the view of some "Ecstasy") and its analogs MDE (methylenedioxy- psychotherapists, a valuable tool for psycholytic ethylamphetamine; psychotherapy. Psycholytic therapies with psyche- dioxoylbutanamine (MBDB) and methoxymethylene- delics (mostly LSD) were performed in many European dioxyamphetamine are ring-substituted and American centers in the 1950s and 1960s. The amphetamine-derivatives. Their chemical structures are rationale of psycholytic therapy has its analogy in closely related to both the stimulant amphetamines and dream analysis: during the psychedelic state defense the psychedelic phenethylamines and methoxyamphet- mechanisms diminish and defended, unconscious amines like mescaline, DOM and DOB (Figure 1). conflict material is visualized in a symbolic way; facilitating the approach to this material for analysis and psychological effects in humans, distinguishing them interpretation after the psycholytic session. Before both from the stimulant and the psychedelic MDMA was scheduled in 1985 it was used by some amphetamines (Shulgin and Nichols 1978, Shulgin therapists, predominantly on the west coast, in indi- 1986). During the last decade, there has been an vidual settings and in marital therapy (Greer and intensive controversial discussion of MDMA in the Tolbert 1990). In Switzerland, a small group of scientific and general media. The dimension of this psychotherapists with still ongoing discussion is motivated by the popularity founded the Swiss Medical Society for Psycholytic of MDMA as an illegal recreational drug (Seymour Therapy in 1988. They obtained time-limited licences 1986, Beck and Morgan 1986, Beck 1990), its for the use of LSD and MDMA in psycholytic sessions neurotoxic potential (Price et al 1989, Grob et al 1990) and treated over a hundred patients with neurotic and and its claimed medical usefulness as an adjunct in psychoreactive disorders during the years 1988 till insight-oriented psychotherapy (Grinspoon and Bakalar 1994 (Styk 1994). Both U.S. and Swiss psycho- 1986, Greer and Tolbert 1986, 1990).
therapists gave enthusiastic reports of the beneficial Studies with laboratory animals demonstrated that effects of MDMA sessions on the therapeutic process high and repeated doses of MDMA cause long-lasting (Greer and Tolbert 1986, Widmer 1989). According to or even irreversible degeneration of brain cells these reports, MDMA helps overcome strong defenses, containing the endogenous transmitter serotonin enables the therapist to confront the patient with deep (Ricaurte et al 1992). This is not a unique finding conflicts by reducing his/her anxiety and may even be with MDMA, because a similar or even stronger the only possibility to overcome stagnation of the neurotoxic potential can be shown in animal studies for psychotherapeutic process in treatment-resistant cases many amphetamines. The clinical significance of these with substantial chronicity. A recent follow-up study experimental data is unclear. However, they built a of 121 treated patients in Switzerland demonstated strong argument for the scheuling of MDMA in 1985.
improvement in 90% of the cases (Gasser, in press).
It was hypothesized that MDMA, MBDB and MDE possesses anxiolytic and antidepressive properties. It constitute a novel psychoactive substance class. Animal evokes a subtle, easily controllable altered state of drug discrimination experiments and pharmacological consciousness with an emphasis on emotional aspects, studies on the structure-activity relationships of relaxation, feelings of happiness, heightened self- MDMA and related compounds support the hypothesis acceptance and empathy, openness for communication of a distinct pharmacological class (Nichols 1986, and decrease of fear responses. In contrast, perceptual Nichols and Oberlender 1990). Nichols (1986) alterations, alterations of thinking and orientation and proposed that the hypothetical new class be designated amphetamine-like stimulatory effects are not generally "entactogens." This new term is composed of the roots"en," "tactus," and "gen" and makes a strong reference The Heffter Review of Psychedelic Research, Volume 1, 1998 to the psychotherapeutic usefulness of the substances.
R = H; Amphetamine R = CH3; MDA, MDMA, MDE R = H, R3 = R4 = OCH3; Mescaline R = CH3; Methamphetamine R = C2H5; MBDB, BDB R = CH3, R2 = OCH3, R4= Br DOBR = CH3, R2 = OCH3, R4 = CH3, DOM Figure 1. Chemical structures of stimulant amphetamines, entactogens, and phenethylamine psychedelics. Nichols (1986): "Just as the word "tact" has the work with MDE, because it was shown to be less connotation of communicating information in a neurotoxic than MDMA in animal studies (Schmidt senstitive and careful way so as to avoid offense, it 1987, Ricaurte et al 1987, Gibb et al 1990). The seemed that the Latin root of this word, tactus, would be appropriate as part of the term. Addition of the placebo-controlled, cross-over, i.e. every volunteer took Greek roots en (within or inside) and gen (to produce) part in one active (a single 140 mg oral dose) and one created the term entactogen, having the connotation of producing a touching within." Fourteen healthy volunteers participated in this However, there are also reports of panic reactions, first study. The psychological effects of MDE were amphetamine-like stimulation and perceptual alterations assessed using several questionnaires and scales. In with recreational MDMA use (Peroutka et al 1988, addition, we studied the neurohormonal influences of Whitaker-Azmitia and Aronson 1989, Dowling et al the drug in eight of the fourteen subjects. The 1987). Reports of recreational users are difficult to remaining six subjects participated in a sleep EEG interpret because of the various influences of the set and study in order to assess the effects of MDE on sleep setting (personality, personal and environmental situative factors) on the effects of the drug and becauseof the frequent concomitant use of other substances or Neurobiological effects of MDE
alcohol. Moreover, tablets sold as "Ecstasy" may Effects on hormonal secretion
contain mixtures of MDMA with amphetamines or The secretion of cortisol, prolactin, and growth even psychedelics or in some cases may lack MDMA hormone is regulated by endogenous transmitters such altogether. In consequence, the position of the as serotonin and norepinephrine acting in the entactogens within the range of the chemically related hypothalamus and hypophyseal gland of the brain. psychotropic drugs is uncertain.
Drugs interacting with these endogenous transmitters(e.g. Human experimental studies with MDE ("Eve")
neurohormonal secretion. Thus, to compare the The most direct way to explore the question of a neuroendocrine effects of psychotropic drugs is one distinct pharmacological entity is to assess the effects of an entactogen in a standardized human experimental setting. Due to the current legal situation, human Eight healthy male volunteers took 140 mg of studies with hallucinogens and related psychoactive MDE or placebo at noon time after a standardized light substances are difficult to realize. However, it is not lunch. For the following 3.5 hours blood samples were impossible to obtain the approvals needed from the taken every 20 minutes for an analysis of the time- responsible state authorities. Our group has already course of the effects on neurohormonal secretion. After performed a pilot study on the subjective and the intake of MDE, there were sharp rises in cortisol neurobiological effects of MDE in healthy volunteers.
and prolactin plasma levels, which declined after about Further studies are currently in progress. We chose to two hours, but were still above the pre-drug level at the The Heffter Review of Psychedelic Research, Volume 1, 1998 end of the experiment. In contrast, growth hormone All subjects displayed a significant stimulation levels did not rise above the pre-drug level (Gouzoulis with increased vigilance, drive and pressure of speech, et al 1993a). From previous studies of other groups it together with sympathomimetic vegetative signs like is known that stimulant amphetamines and psychedelic sweating, slight tremor and moderate rises in blood amphetamine derivatives enhance cortisol and prolactin pressure and heart rate. Most subjects expressed secretion. So, these effects do not differentiate between subjective feelings of increased physical and mental the entactogens and the other chemically related vitality. This amphetamine-like effect pattern was the substances. However, amphetamines are also known to only uniform effect of the drug. enhance the secretion of growth hormone. In our study, The emotional quality of the experience was this was not true for MDE. Our growth hormone data variable. Eleven subjects had an overall pleasant might be indicative of distinct pharmacological experience, which was free of anxiety and included mechanisms supporting the hypothesis of a novel feelings of euphoria, happiness, relaxation, security, and psychoactive substance class (Gouzoulis et al 1993a), self-acceptance. Four out of these eleven subjects were but have to be replicated before further interpretations engaged with important personal themes and were remarkably open for communication in a way thatreminded us of the definition of an "entactogen." It Alteration of sleep architecture
may sound contradictory, but these subjects described In the sleep laboratory study MDE caused mostly, their mood as being "sad." However, they felt at the but not exclusively, amphetamine-like effects. Subjects same time a deep self-acceptance, so the overall took 140 mg MDE or placebo at 11:00 p.m. and experience was very positive. Three out of the eleven lights were switched off immediately. After a normal subjects additionally described cosmic-mystic feelings sleep onset latency and sleep duration of about one (unity with other people and the universe, religious hour, all subjects awoke due to the drug effects and feelings) during the experiment.
stayed awake for at least 2.5 hours during the night on The experience of the remaining three subjects was MDE (Gouzoulis et al 1992). There was a clear very different and included negative emotional feelings. reduction of total sleep time and an increase in One subject reported marked depersonalization and intermittent time awake after MDE. REM sleep, the derealization, blocking of normal thinking and sleep phase with the most prominent dream activity, attenuated emotionality. Another subject had an was completely suppressed and did not occur at all after unpleasant experience of MDE-induced amphetamine- again falling asleep. The effects described so far are like psychomotor excitement and he felt very amphetamine-like. The overall reduction of sleep time dysphoric. Finally, one volunteer experienced a affected all sleep stages, but was more prominent for the psychosis with hallucinations, delusional ideas, functionally less important light sleep (sleep stage 2).
anxious behavior and loss of insight and control of the In contrast, there was a trend towards increase of deep situation for the duration of three hours (Gouzoulis et al sleep (sleep stage 4) during the second part of the night 1993b). All other subjects except this one kept control after MDE compared to placebo, i.e. subjects caught up over their altered state and insight into the experimental with this most restorative sleep phase. Moreover, the nature of their experience. However, half of the subjects cyclic sleep architecture was preserved during the did have some minor perceptual alterations including second part of the night. The missing suppression of mainly visual, but also tactile and auditory phenomena deep sleep and cyclic sleep architecture in the context of e.g. colors were percieved as being more bright, their otherwise amphetamine-like effects is unusual and own own body felt heavier or lighter, etc. These might indicate a distinct effect pattern of MDE on sleep, phenomena and the one case of psychotic reaction are supporting the hypothesis of a novel psychoactive indicative of the underlying hallucinogenic potential of substance class. Interpretation of these data, however, as well as the data on growth hormone secretion, must One of the scales we used is the APZ- be cautious because of the limited number of subjects Questionnaire (Dittrich 1985) for the assessment of (Gouzoulis et al 1992).
altered states of consciousness (ASC), which can beinduced by psychedelic drugs as well as by various psychological conditions such as sensory deprivation oroverstimulation and certain meditation techniques. There was a strong interindividual variability in The items of the questionnaire build three subscales: the psychological effects of MDE (Hermle et al 1993a, the subscale "oceanic boundlessness" (OSE) refers to b). Effects began 30 to 90 minutes after ingestion of the positive emotional states, mystic experiences of unity drug and lasted two to three hours.
and feelings of happiness. The subscale "Dread for Gouzoulis-Mayfrank and Hermle, Entactogens Ego-Dissolution" (AIA) refers to negative emotional literature data, but this procedure has significant experiences with anxiety and panic reactions like a methodological problems. Direct comparative studies horror trip. The subscale "Visionary Restructur- with an entactogen and representatives of the other two alization" (VUS) includes hallucinatory behavior and categories of chemically related phenethylamines will ideas of reference. We compared the mean values of the provide us with stronger evidence for or against the case 14 subjects of our MDE study to the mean values of 12 of a distinct pharmacological class. At present, our volunteers of a former study of our group with the group is conducting an experimental project of this hallucinogenic phenethylamine mescaline (Hermle et al kind in collaboration with the Department of Nuclear 1992). The intake of mescaline resulted in significant Medicine in Aachen (U. Büll), the Psychiatric effects on all three subscales. The effects of MDE were Department of the University of Heidelberg (M.
also significant, but less marked than the effects of Spitzer), the Pharmaceutical Department of the mescaline (Figure 2), the difference being stronger for University of Tübingen (K.-A. Kovar) and the the "negative" and "hallucinogenic" subscales AIA and Psychiatric Department of UC San Diego (M. Geyer).
VUS (Hermle et al 1993a). The MDE-induced state Every volunteer of our ongoing project participates was generally milder, more easy to control and with an in two experimental sessions with the same substance; emphasis on emotional aspects compared to the state this may be MDE, methamphetamine (representative of induced by a classic hallucinogen like mescaline.
the stimulant class), psilocybin (representative of the In summary, the data of our first pilot study with psychedelic class), or placebo. Both the volunteer and MDE are indicative of the close relation of the our team are blind concerning the substance (double- entactogens to both psychedelics and stimulants blind design). Subjects undergo a series of (Hermle et al 1993b). MDMA, MDE and MBDB examinations during the experiments: those include probably take an intermediate position within the range psychopathological of chemically related stimulant amphetamines and computer-based neuropsychological studies of attention hallucinogenic phenethylamines. The entactogenic and memory, PET studies of regional cerebral effects (reduction of anxiety and defenses, self- metabolism, electrophysiological studies of habituation acceptance, empathy, peacefulness) are a major and and pre-pulse inhibition of the startle unique part of the spectrum of action of the entactogens.
assessments of the neuroendocrine secretion and studies However, this spectrum also includes amphetamine- of pharmacokinetics and drug metabolism. With this like and mild hallucinogenic effects.
project, we hope that we will be able to make asubstantial contribution to the understanding of the mechanism of action of the entactogens, as well as the mechanism of action of stimulants and psychedelics.
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Figure 2. Comparison of the altered state of Dittrich, A., von Arx, S., and Staub, S. (1985) consciousness (ASC) induced by mescaline (n = 12) and MDE (n = 14) in healthy volunteers (subscales of consciousness (ISASC). Summary of the results.
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Dowling, G.P., McDonough, E.T., and Bost, R.O.
Ongoing direct comparative studies with MDE
(1987) "Eve" and "Ecstasy": a report of five deaths and other psychoactive phenethylamines
associated with the use of MDEA and MDMA.
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7. Flashbacks in Theory and Practice
Lin S. Myers, Ph.D., Shelly S. Watkins, M.A., and Thomas J. Carter, Ph.D.
Hallucinogenic drugs have been not really bent, although it may look used by humankind for at least five that way. We must remember, though, thousand years. In our society during that our ability the past thirty to fifty years there has perceptual variations been tremendous growth of interest in factors such as cognitive development, and use of psychoactive substances.
brain chemistry, personality, previous experience, and our internal models of recreational, although they have also As we think about the issues raised been used in therapeutic and religious by perceptual variations such as optical illusions, a number of questions governmental and law enforcement come to mind: what is "normal" agencies, and some researchers have consciousness? To what extent can we reflected society's concerns about assume that our experiences are possible dangers of drug use. The fact similar to those of others'? Is there an objective reality independent of our addictive qualities has led to a focus on experience and perception? What role possible long term effects such as do social and cultural systems and flashbacks, a reappearance of the drug expectations play? To what extent and in what ways do our senses and Among the issues we will discuss in this article are what might constitute a flashback, current clinical definitions, overwhelming variety and quantity of some research into the phenomena, perceptual stimuli available to us, how and the implications for therapeutic important are those filters? How are and recreational uses of hallucinogens.
we aware of variations in our own Making sense of flashback phenomena consciousness? Might there be reasons can be difficult because it involves to actively alter our consciousness issues of definitions, consciousness, either through drugs, meditation, or how we recognize qualities of our own mental processes, and interactions These questions, and many others, gain additional importance as we try to understand the effects of what have We attempt to understand the world been called mind-altering drugs, and through our conscious experience.
possible long term consequences of Most people take it for granted that their perceptions are a direct and hallucinogenic substances are LSD, reliable reflection of reality. However, how we perceive the world is a ayahuasca, and ololiuqui. There is a function of both what we take in conservative estimate of one million through our senses and how our brains hallucinogen users in the United States process our perceptions. Without alone (Ott, 1993). The number of students, both in high school and compensate for irregularities in our college, who have used LSD is rising.
perceptual processing. For example, if These current reports have further a myopic person removes their glasses, contributed to concern about safety they don't normally assume that the world has actually become fuzzy. We consequences resulting from drug use. recognize that a stick in the water is Myers et al., Flashbacks Generally, hallucinogenic drugs are so classified largely because of substance, independent of the usual their ability to alter visual perceptions, physiological effects of the substance.
with eyes open or closed, inducing This may include responses to inactive substances (e. g., sugar pills) or patterns, trails of moving objects, unusual responses to active substances.
rippling effects, intensification of For example, heavy users of marijuana colors, and spontaneous formation of may get high smoking marijuana from objects. However, users frequently which all of the active THC ingredient report a variety of other psychological had been removed. This expectation or and perceptual changes including presumption of effect can be powerful alteration of time sense, intense and may influence an individual's experience of emotion (e.g., anxiety, response to a drug. In the 1960s when ecstatic experiences), mood changes (e.g., euphoria, fear), a feeling of mainstream, inexperienced users were unreality or dissociation (out of body given instructions to facilitate a experience), and alterations in the other sensory systems of smell, taste, consideration was given to the setting touch, and hearing. Combination or occurred. Some researchers have sometimes called synesthesia (e.g., suggested that many of the negative "seeing" sounds), experiences with hallucinogens (bad trips) occurred in users who were not As can be seen in the above list, as careful in their attention to set and experiences may be reported setting. Negative experiences have positive, negative, or both. A variety been said to include acute adverse of internal and external factors are known to influence a drug experience.
persistent anxiety, and long term One of the most common factors physiological or perceptual changes.
influencing a person's response to More general social and cultural factors may also play a significant role situation associated with the drug in drug experiences. Various cultures experience. The user's expectations have integrated hallucinogen use into about the drug experience are known their religious and social practices. In as the "set," with the physical location these cultures the set and setting of of the experience known as the drug use fit into a larger context.
"setting." These conceptions help to Visionary and mystical experiences are explain some of the variation in expected and considered an important subjective reports of hallucinogen and positive outcome. There are few effects. If one expects to feel relaxed after smoking marijuana or expects consequences of hallucinogen use in these cultures. This may be a function experience after ingesting psilocybin, of adequate preparation to take these then a set has been established. I n types of drugs, or it may be that such addition, the expectations and attitudes long term effects occur but either are toward a drug experience may be not considered adverse, are not noticed, shared among a group and this may or are not reported because of limited have an effect on experiences of opportunities for investigation or members of the group as well as on treatment. In general, our culture, inexperienced users joining the group.
particularly through the Other psychological effects that can press, has come to interpret possible be experienced with any drug are long term perceptual or psychological known as placebo effects. That is, a changes experienced by hallucinogen person may experience psychological users to be consequences of drug use, The Heffter Review of Psychedelic Research, Volume 1, 1998 and typically they are considered Abraham suggests, based on his adverse effects.
research, that visual disturbances One of the reported primary long occur at a higher rate in people with a term effects occurring with previous history of LSD use. Abraham (1982) hallucinogen use is unexpected recurrence of some or all impairments in color discrimination of the drug experience, called a after prior exposure to LSD. Volunteers flashback. The phenomena associated selected from the outpatient adult with hallucinogenic drug flashbacks have been reported to include relived Massachusetts General Hospital in intense emotion, a feeling of unreality, geometric patterns, trails of moving identifying a white disk, surrounded objects, or a rippling effect. Wesson by a yellow halo, as being white. The and Smith (1976) classified flashbacks from self-reports identification was made was recorded.
including perceptual, somatic, and Following the test, a drug history was emotional types.
taken and the 77 volunteers were The current clinical definition of a divided into three categories: nonusers of LSD (31), and users with and without Persisting Perception Disorder (HPPD) a clinical history of LSD-related described in the flashbacks (10 & 34, respectively). LSD Statistical Manual, 4th edition (DSM- users were defined as persons who IV), of the American Psychiatric reported having used any drug called Association (1994). The definition LSD and having had subsequent changes in mood and perception perceptual symptoms, primarily visual, lasting at least 6 hours. Those who had which must also cause significant social, occupational, or other distress significantly closer to the target to before this diagnosis can be made. The identify it as white compared to visual disturbances controls; however there was geometric hallucinations, flashes of significant difference between LSD color, false perceptions of movement users with and without reported in the visual field, intensified color, flashbacks. Abraham interpreted trails of images of moving objects, these results as suggesting that some LSD users have chronic, irreversible afterimages, macropsia and micropsia.
impairments in color perception. I n The DSM-IV diagnosis is not applicable 1988, Abraham and Wolf published an when the symptoms are associated with additional study of direct measures of another general medical or mental visual perception in which they found condition such as visual epilepsy or that compared to a control group of 20 schizophrenia. It is worth noting that psychiatric outpatients, 24 LSD users, other symptoms reported in research, primarily from the same clinic, had or which have been associated in the impairments in peripheral vision function and had more difficulty phenomena such as anxiety, fear, adjusting to a dark environment.
paranoia, suicidal thoughts, or other In a 1983 paper that foreshadowed emotional or sensory experiences, are what he later defined as HPPD, not included in the diagnostic criteria.
Abraham reports on data collected a The HPPD diagnosis appears to be based decade earlier. In two phases, he had almost exclusively on research by interviewed 123 people with a history Abraham and his colleagues (1982; of LSD use. All participants were 1983; 1988; 1993).
referred to the study in response to anotice in the Acute Psychiatric Service Myers et al., Flashbacks requesting any person ever having studies. A major methodological used LSD. All referrals were made by concern is the makeup of the sample populations. For example, the majority Psychiatry of Massachusetts General of the participants in these studies Hospital in the acute service and the inpatient unit. The volunteers had psychiatric inpatients or people who drug abuse as the most common diagnosis. The 53 volunteers in the treatment. Number of times the drug first phase underwent unstructured, was taken and time since last use open ended interviews about any and varied considerably. Many were polydrug users and were currently resulting from the use of LSD. Of all receiving treatment for substance the symptoms reported, 16 visual abuse or other acute psychiatric disturbances considered by Abraham most compatible with reports in the physiological or psychiatric problems literature of flashbacks were chosen may have been present. These factors for study in phase two, essentially contribute to a lack of generalizability excluding all other reported symptoms of the results to the general population from further study. These visual of hallucinogen users.
Abraham interprets his results as such as geometric hallucinations, implying a causal link between a illusions of movement, trails, flashes of history of LSD use and impairments in color, and prolonged intensification of color discrimination and peripheral color. In phase two, 70 additional vision. However, these individuals may volunteers from the same clinic and a or may not have had these visual disturbances prior to their drug use.
matched for a variety of variables were Since no pre-test was completed, this is given a questionnaire. About 54% of impossible to determine. It is also the 70 users reported having had possible that the dramatic perceptual changes during acute hallucinogen labeled as flashbacks. A number of intoxication allow the individual later issues make it difficult to assess to recognize more readily, non- Abraham's interpretation of these data.
Of the 16 targeted visual disturbances, ordinary perception. Finally, while ten were reported significantly more differences in perceptual factors may often in users than in nonusers.
be present, it was not determined if Abraham then selected the top four they were actually interfering with and found them to have a significant the person's occupational or social functioning in any way.
participants' clinical description of The DSM-IV classification of HPPD is flashbacks, but he may have also problematic for a variety of reasons.
decided thereafter to use these four First is the parenthetical labeling items as his criteria for "flashback".
denoting HPPD as "flashbacks". While Interpretation of his further analyses of variables such as number of uses of LSD and time since last use and their between ever having used LSD and the correlation with "flashback" becomes visual disturbances listed under HPPD, problematic since it is unclear if he means the four visual symptoms or the correlation, that LSD is the sole factor involved in these visual phenomena, is only about 10% of the variance. I n This lack of clarity points to a other words, other factors might have variety of methodological concerns explained his findings in 90% of the regarding the interpretation of these The Heffter Review of Psychedelic Research, Volume 1, 1998 In a 1967 study of 25 emergency room personality factors, etc. Furthermore, patients seen for LSD-related disorders, at no time does he tie a currently over half of them had diagnoses falling experienced "flashback" to a difficulty within the schizophrenia spectrum in discerning visual stimuli during testing. The common conception of a Individuals who may be predisposed to drug flashback is a sudden, unexpected reoccurrence of the drug experience disorganized thought processes are at that is disabling or significantly the highest risk for LSD-related disturbing. His research, which disorders. Conversely, this danger apparently forms the basis for the appears to be low when hallucinogenic DSM-IV classification of HPPD, shows drugs are used by emotionally stable individuals in a safe, protected setting (McWilliams & Tuttle, 1973). An remarks on the stability of the understanding of other personality disturbances over time. Second, the characteristics that may be related to classification suggests any of the drug experiences, reports of long term hallucinogens may be implicated when effects, similar symptom reporting in the majority of Abraham's work has nonusers, and even likelihood of drug focused solely on LSD use.
use itself, is important.
In determining other possible long term physiological effects, the time since the drug was last used (as well as other drugs used) may be important.
ranging from 15 to 77 percent among For example, users who refrained from LSD users. Typically, the samples have using LSD for at least 48 hours before populations and studies have focused orientation and visual perception tests on psychopathology. In the extant when compared to nonusers (Cohen & Edwards, 1969). However, when these restricted populations is sparse. Little tests were administered to LSD users who had not used within one year relationships between more general differences were found between the users and nonusers (McGlothlin et al.
1969). This lack of support for the Our recent study (Watkins et al.
former study suggests that visual and 1995) in a nonclinical sample found perceptual effects may persist for a that of 207 users 21% report ever short time following LSD use, but are having had a drug flashback, while not permanent.
3.3% of the 153 nonusers also reported We should also consider other having had a drug flashback. Users factors that may contribute to both were defined as anyone who had acute and long term responses to hallucinogen. Over half of the users concluded that adverse reactions to reporting drug flashbacks said they marijuana, LSD, and/or mescaline were were not disturbed by them and none related to psychopathology. Others reported being unable to function. In have reported that people at highest contrast, within the nonuser group, risk for adverse reactions tend to have those reporting drug flashbacks were all either moderately bothered or typically ingest high doses more unable to function. Overall, the frequently, and are polydrug users (e.
incidence of flashback reports in this g., Robbins et al. 1967; Smart & sample is at the low end of the range Bateman, 1967; Ungerleider et al. 1968).
described in the literature. Myers et al., Flashbacks Interestingly, we found that the appear not to be warranted from frequency of hallucinogen use, time current research reports.
since last hallucinogen use, and totalnumber of uses had little or no relationship to drug flashback reports.
Time since last use was significantly (1994). Diagnostic and Statistical negatively correlated with reports of Manual for Mental Disorders, (4th HPPD symptoms and not related to self ed.). APA, Washington, D. C.
reports of flashbacks. We also Abraham, H. D. (1982) A chronic examined how personality variables impairment of color vision in users were related to a variety of symptoms of LSD. Brit J Psychiat, 140, 518-
from a sample of DSM-IV diagnostic categories, including HPPD symptoms, and found that in users, scoring higher on measures of fantasy and flashback. Arch Gen Psychiat, 40,
openness to experience were related to reports of having experienced more Abraham, H. D. and Wolf, E. (1988) HPPD symptoms. This study will be Visual function in past users of LSD: reported more fully elsewhere, but Psychosocial findings. J Abn Psych, 97, 443-447.
studying nonclinical samples and investigating other variables that may be relevant to flashback phenomena.
diethylamide. Addiction, 88, 1327-
In this short review we have raised some important issues relevant to Blumenfield, M. and Glickman, L.
future research into hallucinogen (1967) Ten months' experience with flashback phenomena. Examples of LSD users admitted to a county some of the research in this area that psychiatric receiving hospital. NY we have reviewed should underscore State J Med, 67, 1849-1853.
the need for caution in assuming we Cohen, S. and Edwards, A. (1969) LSD already know what the long term and organic brain impairment.
Drug Dependence, 2, 1-4.
hallucinogen use may be. Much of the published literature (see for example Freedman, D. (1969) Organicity measures following repeated LSD ingestion. Arch Gen Psychiat, 21,
organic changes or alterations of McWilliams, S. and Tuttle, R. (1973) controversial but tends to suggest that Long-term psychological effects of most such possible LSD. Psych Bull, 79, 341-351.
relatively benign. As previously Naditch, M. (1974) Acute adverse mentioned, in our study of nonclinical reactions to psychoactive drugs, participants who were hallucinogen drug usage, and psychopathology. J Psychoactive Drugs, 22, 305-311.
rendered them unable to function, and Kennewick, WA. Natural Products, most considered the experience not to be bothersome. While care must Ungerleider, J. and Fisher, D. (1967) certainly be taken in the use of psychoactive substances of any type in emotional disorders. Cal Med, 106,
recreational contexts, concerns about Watkins, S., Carter, T. J., and Myers, L. S.
(1995) Hallucinogen flashbacks: The Heffter Review of Psychedelic Research, Volume 1, 1998 Reality or myth? Poster (88.5)presented Neuroscience meeting, November,1995.
Wesson, D. R. and Smith, D. E. (1976) An flashbacks. Amer J Drug Alcohol
Abuse, 3, 425-438.
8. Ten Year Study of Ketamine Psychedelic Therapy (KPT) of Alcohol Dependence
Evgeny M Krupitsky, M.D., Ph.D. and A.Ya Grinenko, M.D., Ph.D.
Psychedelic psychotherapy was shown to be a Two-year follow-up data had been collected for potential benefit for alcoholism treatment in the the 81 patients who had undergone the KPT (because "60s," but different methodologies made it difficult to at the moment of the follow-up study only 81 out of generalize across studies. The requisite development 111 patients had a two-year follow-up period after of appropriate sophistication for these studies was not KPT). According to the data, abstinence of more possible to do after they were scheduled in 1970 and than 2 years was observed in 33 out of these 81 their use was strictly limited. However, at about this patients (40.7%). Thirty-eight patients (46.9%) had time, ketamine was being relapsed. We could not obtain two-year follow-up "psychedelic" emergent phenomena in patients. This data on 10 patients (12.4%). Three-year follow-up property of ketamine was exploited by our use of data had been collected for the 42 patients who had ketamine-assisted therapy of alcoholism. Ketamine undergone KPT. According to the data, abstinence of has some advantages over other psychedelics as an more than 3 years was observed in 14 out of these 42 adjunct to psychotherapy. It is safe and short acting patients (33.3%). Twenty-four patients (57.2%) had (the psychoactive effects lasting about an hour). In relapsed. We could not obtain three-year follow-up addition, ketamine is not scheduled like other data on four patients (9.5%). These two- and three- psychedelics. In lower doses (about one sixth to one year follow-up data are also evidence of the high tenth of that usually used in surgery for a general efficacy of KPT.
anaesthesia) it induces a profound psychedelic We also carried out psychological, biochemical, and neurophysiological studies of the different Psychotherapy in our model consists of the possible underlying mechanisms of KPT.
preparation of patients for the psychedelic session, thepsychotherapeutic facilitation of the session and Psychological underlying mechanisms
special post-session 1992). This post-session work is intended to help the patient integrate insights from the psychedelic All patients in each experimental group were experience to the everyday life and relate the experience to his life and personality problems.
Personality Inventory (MMPI) (adapted in Russia by Moreover, psychotherapy in this manner acquires a Sobchik (1990)) before and after KPT.
special quality. It is considered here not only as a According to the MMPI data, our analysis of process of resolution of certain psychological psychological changes in the experimental group problems, but also as an important stage in spiritual points to definite, rather expressed dynamics in the maturation. The uniquely profound and powerful patient's MMPI profiles. Particularly, after KPT the psychedelic experience often helps our patients to indices were decreased for the majority of the main generate new insights that enable them to integrate MMPI scales. The most expressed, statistically new, often unexpected meanings, values and attitudes significant decrease in the profile was in the scale about their individual selves and the world.
"hypochondria," "depression," We carried out a controlled clinical trial of the "psychastenia," efficacy of KPT. To determine the efficiency of the repression," and also in Taylor's scale of anxiety. At treatment, we collected follow-up information about the same time, the estimate in the Ego strength scale all the patients who had taken part in this study a year after their release. According to the data, psychological dynamics testify to the fact that the abstinence of more than 1 year was observed in 73 patients became more sure of themselves, their out of 111 people (65.8%) who had undergone the possibilities, their future, less anxious and neurotic, KPT. Thirty people (27.0%) had relapsed. We and more emotionally open after KPT. Against the could not obtain data on eight patients (7.2%). In background of these general tendencies, we saw in the the control group of 100 patients whose treatment majority of cases some essential individual variations consisted only of conventional methods, only 24 (e.g. concerning changes in such patients (24%) remained sober for more than 1 year (p < 0.01). Thus, the data from the follow-up study and "sensitivity-repression") that reflected, as a rule, a demonstrated that ketamine-assisted psychedelic certain harmonization of the patient's personality therapy increases the efficacy of conventional Krupitsky and Grinenko, Ketamine therapy in alcoholism Locus of Control
One should also underline the fact that, according Thirty alcoholic patients treated with KPT were to the CTA data, there occurred strong positive examined with the Locus of Control Scale (LCS) developed by J.Rotter (Phares, 1976) and adapted in Russia by Bazhin et al. (1993). All patients were psychotherapist, close relatives, to the image "Me assessed with the LCS twice: before and after KPT.
sober," and to the ideal image of self. This means It was established that locus of control in the that the patient has internally grown to emotionally personality of alcoholic patients became significantly accept these images and, in turn, the attitudes toward more internal after KPT (from 11.1 ± 4.8 to 30.3 ± sobriety connected with them. Thus KPT of 5.3; P<0,01). This means patients became more sure alcoholism may be of benefit by transforming about the ability to control and manage different unconscious attitudes, particularly those related to situations of their life, they became more responsible sobriety. The enhancement of the relationship to the for their life and future after KPT.
therapist may have enhanced transference issues whichmay also have had a therapeutic effect.
A special note should be made of the discrepancies between the verbal and nonverbal Color Test of Attitudes and Personality Differential
estimates of a patient's personal attitudes registeredbefore KPT. These discrepancies, obviously, reflect We also studied changes in the psychosemantic the presence of an essential discord between the domain induced by KPT. The study used the data from 69 alcoholic in-patients treated with KPT in our personality's attitudes. This discord reflects a hospital. All patients were examined by the peculiar difference between the subject's unconscious personality differential test (PD) (Bazhin and Etkind, and conscious mind, and possibly characterizes the 1983) (a personality oriented version of Osgood's ambivalence of the patient's position and the semantic differential (Osgood et al., 1957)) and also disagreement between what is declared at the verbal by the color test of attitudes (CTA) (Etkind, 1980) level and what takes place at the level of the before and after the treatment.
immediate emotional experience. Such discord may The analysis of the CTA results revealed that give rise to psychological discomfort, internal after KPT there occurred significant positive changes tension, to difficulties in communication with the environment, i.e. to the reduction of a person's psychotherapist, close relatives, to the ideal image of adaptation, which after all leads to alcoholism self, and to the image "Me sober," At the same time, relapse. Therefore, the reduction of such discord due the attitude to the image "Me drunk" became more to KPT should be considered as an achievement of a negative. According to the PD data, significant personality's psychologial status positive changes occurred after KPT only in respect to the attitude toward the person himself (Krupitsky,1992).
After KPT there occurred a considerable decrease A study with repertory grids (Kelly matrixes)
in differences between certain indicies of the CTA and Ten alcoholic patients were tested with verbal that of PD in respect to the same images. This and special nonverbal (color) repertory grids before decrease was evidenced by the reduction of the KPT and after it. Then we calculated the mean difference between the verbal (realized) and nonverbal verbal repertory grid (MVRG) and mean color (unrealized) assessments of personal attitudes. Such (nonverbal) repertory grid (MCRG) for all 10 patients reduction was mainly related to the change in the together. Four MVRG and MCRG (2 before KPT CTA indices and appeared to be the strongest for the and 2 after KPT) were processed by the standard sphere of attitudes to a psychotherapist, relatives, the programs of repertory grid computer-assisted analysis image "Me sober," and the ideal image of self.
(Fransella and Bannister, 1977), and then semantic spaces of the personality were built (Fig. 1 and 2).
significant positive changes in the domain of The semantic space of the personality (built on the personality attitudes, which took place due to the basis of multidimentional assessments of elements transformation of nonverbal (unrealized) emotional with constructs) shows semantic interrelationships attitudes. KPT resulted in a decreased level of and interconnections between elements and/or dissonance between isosemantic indices as measured constructs of the repertory grid.
by CTA and PD which could be interpreted as areduction of dissonance between verbal/conscious andnon-verbal/unconscious regarding alcohol use and personality characteristicsand relationships. The Heffter Review of Psychedelic Research, Volume 1, 1998 (A) Before KPT
(A) Before KPT
ideal image of self ideal image of self recovering alcoholic recovering alcoholic (B) After KPT
(B) After KPT
recovering alcoholic recovering alcoholic Figure 1. Semantic space of the mean color Figure 2. Semantic space of the mean verbal repertory grid of alcoholic patients repertory grid of alcoholic patients The results of this study have demonstrated The changes in the verbal repertory grids were some positive changes in the semantic space of the not so significant as in the color repertory grids personality of alcoholic patients, particularly in the (Fig.2A and 2B). The image "Drunkard" only space of personality characteristics of the color became a little bit more distant from the group of repertory grids. The image "Me now" was close to positive images and closer to the image "Me in the the image "Drunkard" and far from the group of such past." It is interesting to note that patients already positive images as "Recovery alcoholic," "Ideal identified themselves with positive images at the image of self," "Wife," "A man who gets on in life," level of verbal self-identification in the semantic space and others in the semantic space of the MCRG before of personality characteristics and value orientations KPT (Fig.1A). After KPT the image "Me now" before KPT, whereas they identified themselves in the became close to the group of positive images same way at the level of nonverbal (unaware, mostly described above and far from the image "Drunkard" in emotional) perception only after KPT. This can be the space of MCRG (Fig.1B). At the same time the interpreted to mean, first of all, that KPT creates a image "Drunkard" became closer to the image "Me in profound nonverbal association with the sobriety self- the past." These data indicate that alcoholic patients concept, and second, that KPT brings about the emotionally perceived (identified) themselves as attainment of similarity (resemblance) of verbal drunkards before KPT. After KPT their emotional (realized) and nonverbal (unaware) perception by the perception of themselves had been changed: they patients of their individual self and the world.
emotionally identified themselves with "recovery alcoholic" and other positive images in the semantic transformed primarily the nonverbal (unaware, mainly space of personality characteristics and value emotional) perception by alcoholic patients of their orientations, and identified themselves as drunkards individual self. Thus, it is possible to conclude that only in the past.
KPT positively transformed mostly the emotionalself-identification (self-concept) of alcoholic patients.
Content Analysis Data
content-analysis of psychedelic experiences written down by our patientsafter their KPT sessions. It is of interest to note thata content analysis from the written self-reports of 108male Krupitsky and Grinenko, Ketamine therapy in alcoholism which considers alcoholism as an "existential demonstrated a number of statistically reliable neurosis," as a consequence of losing the meaning of correlations between some MMPI scales and the life and the appearance of a specific "existential void" content of the psychedelic experience described in (Frankl, 1978), which KPT we believe is able to fill, self-reports. Thus, one may conclude that the at least to some extent.
ketamine psychedelic experiences are to a certainextent determined by the personality characteristics of Effect on Spirituality
We have studied the influence of a profound In addition we also have demonstrated the mystical (transformative) experience during KPT on the level of spiritual development of the alcoholic between the content of the ketamine session patients in this study. For the assessment of changes experiences and the MMPI profile changes caused by of spirituality we used our own special Spirituality KPT. That is, the content of the ketamine session Scale based on a combination of the Spirituality Self- experiences to a certain extent determines the Assessment Scale developed by Charles Whitfield, personality changes caused by KPT.
who studied the importance of spirituality inalcoholism Effect on Life Values
(Whitfield, 1984), and the Life Changes Inventory Thirty patients assessed with the LCS were also developed by Ken Ring to estimate the changes of examined with the Questionnaire of Terminal Life values and purposes of life produced by near-death Values ( QTLV ) developed by Senin (1991) and experiences (Ring, 1984). It was demonstrated by based on Rokeach's approach to human values and our Spirituality Scale that the increase in the level of beliefs (Rokeach, 1972, 1973). Patients were spiritual development of our alcoholic patients due to examined with QTLV twice: before and after KPT.
KPT was comparable to the increase induced in This study has demonstrated a number of healthy volunteers by a special course of meditation significant positive changes in patient's values as a and was much greater than the changes in spiritual result of KPT. KPT enhanced the importance of such development induced in alcoholics by a training life values as creativity, self-perfection, spiritual program of relaxation techniques and self hypnosis contentment, social recognition, achievement of life (autogenic training). It is evident that the increased purposes and individual independence. These spiritual development induced by KPT in alcoholic changes were mostly expressed in such areas of life patients is very auspicious for sobriety. Moreover, values actualization as family, education and social the results of the study of KPT's influence on life. It is evident that such a positive transformation spirituality demonstrate that KPT is much more than of a patient's life values system brings about enhanced simply the creation of an attitude in alcoholic patients motivation for a sober life and favors sobriety.
toward a sober life. These results show that KPTbrings about profound positive changes in life values Effect on grasping the meaning of life (purposes
and purposes, in attitudes toward the different aspects of life and death, and, in turn, in the alcoholic's world Ten alcoholic patients were studied before and view. Many reports suggest religious or spiritual after KPT with the Purpose-in-Life Test (PLT) conversion as an important factor in "spontaneous" elaborated by Crumbaugh (1968) and based on recovery from drug abuse, and Alcoholic Anonymous Frankl's concept of man's aspiration for the meaning of life. The PLT was adapted in Russia by Leontiev orientation (Whitfield, 1984; Corrington, 1989; Grof, (1992) in the Department of Psychology of the 1990). A therapy that enhances the likelihood for a Moscow State University.
conversion type experience therefore might have This study has shown that KPT causes a utility in the treatment of substance abuse.
significant increase in the index of grasping the meaning of life in alcoholic patients (from 89.7 ± 5.7 represent one method to elicit religious spiritual to 115.3 ± 3.2; p < 0.01). Before KPT, the index experience in patients with chemical dependence.
was below the average normal level, but after KPT it Thus, KPT brings about positive changes in was greater. These changes mean that after KPT characteristics, nonverbal emotional patients were able to grasp better the meaning of their attitudes and self-concept, positive transformation of lives, their life purposes, and perspectives. Their life value orientations and grasping the meaning of life, became more interesting, emotionally saturated, and and also spiritual growth. All these psychological filled with meaning for them after KPT. They felt changes favor a sober life.
themselves more able to live in accordance with theirconcept of the meaning of life and life purposes as a Underlying Biochemical Mechanisms
result of KPT. Such changes favor a sober life, We also carried out biochemical investigations of particularly from the standpoint of Frankl's approach the underlying mechanisms of KPT. The results of The Heffter Review of Psychedelic Research, Volume 1, 1998 the biochemical investigations have shown that alcoholic patients (Ivanov et al., 1995). Sixty-four during the ketamine session there occurred a real alcoholic patients with different personality disorders decrease in the activity of MAO-A in blood serum (avoidant - 20 patients, histrionic - 21 patients, and and MAO-B in blood platelets, and there also was an borderline - 23 patients) were treated with KPT.
increased dopamine level in blood. Plasma serotonin Data from clinical (Bekhterev Psychoneurological concentrations were not Research Institute rating scales) and psychological significantly. An increase of ceruloplasmin activity (MMPI, Spielberger State-Trait Anxiety Scale, T.
was statistically significant and the (-endorphin level Leary test of interpersonal relationships) studies increased during the KPT session (Krupitsky et al., psychedelic psychotherapy in the different groups of Changes in neurotransmitter metabolism could patients. KPT proved to be very effective in patients have some notable aspects. First, they allow some with avoidant personality disorders, less effective in speculations about the underlying neurochemical patients with histronic personality disorders and least mechanisms of the psychedelic action of ketamine effective in patients with borderline personality (Krupitsky et al., 1990). For example, an increase of disorders. It should be noted that KPT positively ceruloplasmin activity causes a influenced on the personality characteristics assessed increase in the conversion of monoamines into by MMPI in all groups of alcoholic patients with adrenochromes which have been speculated to possess hallucinogenic activity. This would be particularly The potential of ketamine-assisted psychedelic true under conditions of inhibited MAO activity and therapy is not restricted to the treatment of addiction.
increased dopamine levels. It is of interest that such According to data from our pilot study (20 patients, 7 conditions occur during the action of many male and 13 female), ketamine-assisted psychedelic hallucinogens (Hamox, 1984; McKenney et al., therapy is also quite effective in treating neurotic disorders. This research has demonstrated that the Second, the fact that the pharmacological action efficacy of ketamine psychotherapy differed with of KPT affected both monoaminergic and opioidergic various forms of neuroses: psychedelic therapy proved systems, i.e. those neurochemical brain systems that treating neurotic (reactive) are involved in the development (pathogenesis) of depression and post-traumatic stress disorders, and alcohol dependence, is an important result of this least effective in treating obsessive-compulsive and biochemical investigation. It is possible that these phobic neuroses. Hysterical neurosis appeared to be changes are related to a certain extent to the efficiency most resistant to psychedelic therapy.
of this method.
We have been working with KPT since 1985 According to the data from computer-assisted and have already treated more than 1000 alcoholic EEG analysis we discovered that ketamine increases patients with KPT without any complications such delta activity (a 1.5-2 fold increase) and particularly as protracted psychoses, flashbacks, agitation, or theta activity (a 3-4 fold increase) in all regions of the ketamine abuse. KPT appears to be a safe and cortex. This is evidence of limbic system activation effective method for treatment of alcohol dependence.
during ketamine sessions, as well as evidence for the It seems to be an especially powerful tool in Russia, reinforcement of the limbic-cortex interaction. This where there was no psychedelic revolution in the fact can also be considered to a certain extent to be 1960s, where almost no one knows the meaning of indirect evidence for the strengthening of the "psychedelic," or can even imagine that this drug interactions between the conscious and subconscious might be used for recreation, or for fun. In Russia, levels of the mind during the KPT.
therefore, KPT looks particularly unusual andpowerful.
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ketamine, which allows for the maintenance of a Bazhin, E.F. and Etkind, A.M. (1983). A constant verbal relationship with the patient. We Manual for Personality Differential. Leningrad (in believe that KPT might induce in some drug abusing patients the same psychotherapeutic effects that we Corrington, J.E. (1989) Spirituality and have seen in alcoholics.
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Karandashova, G.F., Berkaliev, T.N., Moshkov,K.A. and Borodkin, Yu.S. (1990) Metabolism ofbiogenic narcopsychotherapy with ketamine administration.
Biogenic Amines 7, 577-582.
Leontiev, D.A. (1992) Test of the meaning of life orientations. Smisl, Moscow (in Russian).
McKenney, T.D., Towers, G.H.W. and Abbots, T.S. (1984) Monoamine oxidase inhibitors in SouthAmerican hallucinogenic plants. Part 2: Constituentsof orally-active Myristicaceous hallucinogens. J.
Ethnopharmacol. 12, 179-211.
Osgood, Ch., Susi, C.J. and Tannenbaum, P.M.
(1957). The Measurement of Meaning. Urbana.
Phares, E.J. (1976) Locus of Control in Personality. New York.
Ring, K. (1984) Heading Toward OMEGA.
William Morrow and Company, Inc., New York.
Rokeach, M. (1972) Beliefs, Attitudes and Values. Josey-Bass Co., San Francisco.
Rokeach, M. (1973) The Nature of Human Values. Free Press, New York.
Senin, I.G. (1991) Questionnaire of Terminal Life Values. Yaroslavl (in Russian).
9. New Views of Timeless Experiences: Contemporary Research on the Nature and
Significance of Transpersonal Experiences
Roger Walsh, M.D., Ph.D.
If there is one thing that is clear about The Evolution of Our Understanding
psychedelics it is that they can unleash an awesome In psychiatry, it was Freud who set the original variety of experiences. Some of the most powerful, as tone. The title of his book The Future of an Illusion well as the most profound and transformative are also left little doubt about his views on the nature of religion. He regarded it as a developmental relic to transpersonal experiences in which the self-sense be outgrown and mystical experiences as severely expands beyond (trans) the personal or personality to regressive. Nor were Western religions the only ones encompass wider aspects of humankind, life, the to be dismissed. In a well known text The History world and the universe.
of Psychiatry, Alexander & Selesnick (1966) pointed Some of these echo experiences that have long to "the obvious similarities between schizophrenic been the goal of the world's great spiritual- regressions and the practices of yoga and Zen." contemplative traditions and in certain cases appear Of course such views were understandable, given phenomenologically indistinguishable that mental health practitioners were seeing disturbed blown mystical experiences, as Walter Pahnke individuals whose relationships to, and use of, demonstrated in his famous Harvard chapel Good religion were often also correspondingly disturbed.
Friday study. Some researchers, e.g. Zaehner, have Moreover, this dismissive trend also reflected a argued that drug induced experiences could not larger, centuries-long trend in Western culture.
possibly be the same as those that contemplatives Beginning with the age of enlightenment, the rise of labor for decades before tasting. However the science had performed the healthy and much needed religious scholar Huston Smith (1964/1993) seems to function of freeing European civilization from the have demolished this claim in his classic paper "Do stifling grip of the church's dogmatic control.
drugs have religious import?" and theoretical Within a mere evolutionary blink of the eye the arguments for their identity have also been advanced dominant arbiters of reality shifted from church and (Stace, 1987; Walsh, 1991).
clergy to science and scientists.
Yet even if some psychedelic experiences are The peak--or nadir, phenomenologically indistinguishable from classic perspective--of this shift was symbolized by Auguste contemplative and mystical experiences this is Comte, founder of positivism. To satisfy the needs certainly not enough to establish their significance of the unsophisticated masses, Comte proposed a new and value in the eyes of many contemporary church complete with scientists as saints. Comte academicians and mental health professionals. For to modestly allowed that he would be willing to serve many such people religious experiences themselves as pope; but alas, he became increasingly grandiose are suspect and may even be taken as evidence of and died deranged. Yet Comte notwithstanding, psychopathology. Such views reflect both the history science continued to pour forth its marvels and the of psychiatry and much of the modern and human vision of the universe expanded from leagues postmodern cultural zeitgeist. Yet it is increasingly to light years, and from countries to the cosmos.
clear that such pathologizing interpretations are no Yet in other ways the human vision of the longer tenable in the light of recent research. The universe and of ourselves was curiously diminished.
aim of this article is therefore to trace the evolution of Whereas the scope of the known universe kept our understanding and to make clear that observations expanding, its meaning and significance kept of the power and potential benefits of transpersonal contracting. Comforted by the great religious myths, experiences, whether psychedelically or contem- humans had once felt themselves to be children of platively induced, are fully consistent with con- God, at home in a coherent, divinely ordered world temporary research and theory.
designed expressly for their wellbeing. Now theysaw themselves as meaningless blobs of protoplasm,adrift on an uncaring speck of dust in a remoteunchartered corner of one of uncountable billions ofgalaxies. Human beings were increasingly demotedto mere sophisticated machines: the "stimulus-response machines" of behaviorists, the "wet Walsh, Timeless Experiences order into this semantic chaos. One useful approach evolutionary biologists pecularily baroque is to look at religion and spirituality from a example of the lengths to which nuclear acid is developmental life-span perspective.
prepared to go to copy itself" (Chedd, 1973).
Researchers increasingly divide development into Of course mind and transcendental experiences three major phases: preconventional, conventional were similarly deflated. Mind came to be regarded as and transconventional; or prepersonal, personal, and epiphenomenon of the transpersonal. Whether it is the development of machinery of the cognition, morality, faith, motivation or a self-sense, experiences were dismissed as the disordered fire- it is clear that we enter the world unsocialized (at a works of that machinery. Francis Crick, discoverer of preconventional stage) and are gradually acculturated the nature of DNA, epitomized this view with his into a conventional worldview and modus operandi.
suggestion that belief in the existence of God might be due to mischievous mutant molecules that he postconventional stages of post-formal operational named "theotoxins." cognition (see, for example, the work of Flavell and Consequently, all meaning, purpose and values-- transconventional no matter how venerated or venerable -- suddenly Kohlberg), universalizing faith (James Fowler), self- seemed groundless. The net result was what Lewis actualizing and self-transcending motives (Abraham Mumford described as "a disqualified universe," and Maslow), and a transpersonal self-sense (Ken Wilber).
what the sociologist, Max Weber, called "the These diverse studies have been synthesized into a disenchantment of the world." This disenchanted remarkably comprehensive theory of transpersonal world was now reduced, as the Nobel Laureate development by Ken Wilber (1981, 1986).
philosopher of science Alfred North Whitehead (1967) What is crucial for a contemporary psychological lamented, to merely "a dull affair, soundless, understanding of religion is the recognition that scentless, colorless; merely the hurrying of material, religious belief, behavior and experience can occur at any stage --preconventional, conventional or post- And yet, as Whitehead pointed out "this conventional-- and can vary dramatically in form, position on the part of the scientist was pure bluff." function and value according to the stage. There is Scientists had made the understandable but disastrous no question that religion can be tragically misused in mistake of sliding from science into scientism; from the service of, for example, egocentricity, bias and believing that science was a superb way of gaining fanaticism. But the great mistake of many scientists some information about some things to believing it and mental health practitioners who dismissed was the best or only way of obtaining information religion wholesale was to mistake parts about all things; from saying that what science can't preconventional or conventional religion for all of observe it can't observe to saying that what science religion; to equate dogmatic mythical or magical can't observe doesn't thinking with all religious thinking; to fixate on religion as a defensive maneuver and overlook Yet as with so many things, the times are religion as a developmental catalyst; to conflate changing, and with them our views of science, preconventional regression with transconventional religion and transpersonal experiences. It is now progression; and to confuse the schizophrenic's increasingly clear that the reductionistic dismissal of prepersonal loss of ego boundaries with the mystic's religion by science and its pathologization by transpersonal recognition of the unity of existence.
psychiatry are largely based on unsophisticated views The net effect is what is now known as "the of science, religion and transpersonal experiences.
pre/trans fallacy": the confusion and conflation of While there is much in religion that is problematic there is also much that is beneficial.
stages with transconventional/transpersonal stages.
Science is only one way of obtaining valid Henceforth we will need to be far more precise in information. For a comprehensive view of ourselves identifying the function and developmental level of and the world, it needs to be complimented by religious behavior, belief and experience.
(hermeneutical), Fortunately, relevant research on religion, introspective modes of knowing. In addition, a spirituality and transpersonal experiences is expand- materialistic, reductionistic, disqualified worldview of ing dramatically and includes some of the following nature and humans--so long assumed to follow helpful background findings.
naturally and necessarily from science--is only one of Growing numbers of contemporary psychoana- many possible views.
lytic thinkers are forging new psychoanalytic perspec- It is now clear that the terms religion and tives of religion and no longer see psychoanalysis and spirituality can refer to so many different behaviors, authentic spirituality as incompatible. People who values and institutions that understanding them and have transpersonal or mystical experiences, far from their psychological significance requires bringing The Heffter Review of Psychedelic Research, Volume 1, 1998 being necessarily pathological, score above average Stace, W. (1987) Mysticism and Philosophy. Los on multiple measures of well-being.
Angeles: J. Tarcher.
Several hundred studies of meditation confirm Walsh, R. (1990) The Spirit of Shamanism. Los that, in addition to inducing the transpersonal Angeles: J. Tarcher.
experiences that are its goal, it can produce wide- Walsh, R., Vaughan F., eds. (1993) Paths Beyond ranging psychological, physiological and biochemical Ego. Los Angeles: J.P. Tarcher.
effects and therapeutic benefits. Intriguing findings West, M, ed. (1987) The Psychology of Meditation.
include evidence for enhanced creativity, perceptual Oxford:Clarenden Press sensitivity, empathy, marital satisfaction, lucid Whitehead, A. (1967) Science and the Modern dreaming, sense of self-control, and self-actualization.
World. New York: Macmillan.
Developmentally, several studies suggest it may Wilber, K. (1980) The Atman Project. Wheaton, foster maturation on scales of ego, moral and cognitive development. Clinical research suggests Wilber, K. (1983) Eye to Eye: The Quest for the that it can be therapeutic for several psychological and New Paradigm. Garden City: Anchor/Doubleday.
psychosomatic disorders including anxiety, phobias, Wilber, K., Engler, J., Brown, D., eds. (1986) posttraumatic stress, insomnia, drug abuse, chronic Transformations of Consciousness: Conventional pain and mild depression (West, 1987; Walsh & Vaughan, 1993).
Development. Boston: New Science Library/ transpersonal experiences and whatever their precisenature may finally turn out to be, are far from beingsigns of severe pathology as was once widelyassumed. Rather they seem to be followed bysurprisingly large, long lasting and beneficialpsychological changes, especially associated withdecreased concern with materialism and increasedinterest in love and learning.
In the new psychiatric diagnostic manual, DSM- IV, a new category for religious or spiritual problemsrefers to religiously based difficulties that do notreflect pathology. This new code is an importantstep in institutionalizing the recognition thatreligious interests, concerns and experiences are notsynonymous with pathology.
Together, these findings make abundantly clear that transpersonal experiences are far from beingsynonymous with pathology. Rather, they can besurprisingly beneficial and transformative and aremost likely to occur in people of exceptionalpsychological health and maturity. These facts, plustheir remarkable frequency and power in psychedelicsessions, suggest that they deserve to be a focus offurther psychedelic research.
Alexander, F., Selesnich S. (1973) The History of Psychiatry. New York: New American Library.
Chedd, G. (1973) New Scientist. 58:606-608.
Freud, (1928/1955) The Future of an Illusion. NewYork: H. Liveright Publishing Corporation.
Smith, H. (1964) Do drugs have religious import? (1993) The Journal of Philosophy, LXI, 517-530. Reprinted in R. Walsh & F. Vaughan eds.
Paths Beyond Ego: The Transpersonal Vision.
Los Angeles: J. Tarcher, pp 91-93.
10. The Scientific Investigation of Ayahuasca: A Review of Past and Current Research
Dennis J. McKenna,1 Ph.D., J. C. Callaway, Ph.D.,2 and Charles S. Grob. M.D.3 ayahuasca can conveniently be divided into a Of the numerous plant hallucinogens utilized by consideration of its use among indigenous aboriginal indigenous populations of the Amazon Basin, and mestizo populations, and its more recent perhaps none is as interesting or complex, contemporary syncretic religious botanically, chemically, or ethnographically, as the movements such as the União do Vegetal (UDV), Barquena, and Santo Daime sects in Brazil. It is ayahuasca , caapi, or yage. The beverage is most within the context of acculturated groups such as widely known as ayahuasca, a Quechua term these that questions regarding the psychological, meaning "vine of the souls," which is applied both to medical, and legal aspects of the use of ayahuasca the beverage itself and to one of the source-plants become most relevant, and also, most accessible to used in its preparation, the Malpighiaceous jungle liana, Banisteriopsis caapi (Schultes, 1957). In The use of ayahuasca in the context of mestizo Brazil, transliteration of this Quechua word into folk medicine closely resembles the shamanic uses of Portuguese results in the name, Hoasca. Hoasca, or the drug as practiced among aboriginal peoples. In ayahuasca, occupies a central position in Mestizo both instances, the brew is used for curing, for ethnomedicine, and the chemical nature of its active divination, as a diagnostic tool and a magical constituents and the manner of its use makes its pipeline to the supernatural realm. This traditional mode of use contrasts from the contemporary use of neuropharmacology, neurophysiology, ayahuasca tea within the context of Brazilian syncretic religious movements. Within these cults,the members consume ayahuasca tea at regular Traditional and Indigenous Uses of Ayahuasca
intervals in group rituals in a manner that moreclosely resembles the Christian Eucharist than the The use of ayahuasca under a variety of names traditional aboriginal use. The individual groups of is a widespread practice among various indigenous the UDV, termed nucleos, are similar to a Christian aboriginal tribes endemic to the Amazon Basin Hutterite sect, in that each group has a limited (Schultes, 1957). Such practices undoubtedly were membership, which then splits to form a new group well established in pre-Columbian times, and in fact once the membership expands beyond the set limit.
may have been known to the earliest human The nucleo consists of the congregation, a group inhabitants of the region. Iconographic depictions on leader or mestre, various acolytes undergoing a course ceramics and other artifacts from Ecuador have of study and training in order to become mestres, and provided evidence that the practice dates to at least a temple, an actual physical structure where the 2000 B.C. (Naranjo, 1986). Its widespread sacrament is prepared and consumed at prescribed distribution among numerous Amazonian tribes also times, usually the first and third Saturday of each argues for its relative antiquity. month. The membership of these newer syncretic Considerable genetic intermingling and adoption groups spans a broad socio-economic range and of local customs followed in the wake of European contact, and ayahuasca, along with a virtual professionals (including a number of physicians and pharmacopoeia of other medicinal plants, gradually other health professionals). Some older members became integrated into the ethnomedical traditions of have engaged in the practice for 30 or more years these mixed populations. Today the drug forms an without apparent adverse health effects. The UDV and important element of ethnomedicine and shamanism the Santo Daime sects are the largest and most as it is practiced among indigenous Mestizo visible of several syncretic religious movements in populations in Peru, Colombia, and Ecuador. The Brazil that have incorporated the use of ayahuasca sociology and ethnography of the contemporary use of into their ritual practices. Of the two larger sects, it ayahuasca (as it is most commonly termed) in organizational structure as well as the most highly described (Dobkin de Rios, 1972, 1973; Luna, 1984, disciplined membership. Of all the ayahuasca churches in Brazil, the UDV has also been the most Syncretic Religious Use of Ayahuasca
pivotal in convincing the government to remove From the perspective of the sociologist or the ayahuasca from its list of banned drugs. In 1987, the ethnographer, discussion of the use of ayahuasca or government of Brazil approved the ritual use of 1 Heffter Research Institute, Santa Fe, NM 2 Department of Pharmaceutical Chemistry, University of Kuopio, Finland 3 Heffter Research Institute, Santa Fe, NM, and Department of Psychiatry, Harbor/UCLA Medical Center McKenna et al., Investigation of ayahuasca hoasca tea in the context of group religious interactions of such agents with serotonergic agonists ceremonies. This ruling has potentially significant and MAO inhibitors are essentially unknown in implications, not only for Brazil, but for global drug modern medicine. policy, as it marks the first time in over 1600 yearsthat a government has granted permission to its non- 2. Chemistry of Ayahuasca and its source plants
indigenous citizens to use a psychedelic in the The chemical constituents of ayahuasca and the context of religious practices.
source-plants used in its preparation have been wellcharacterized (McKenna, et al., 1984; Rivier & Botanical, Chemical, and Pharmacological
Lindgren, 1972). Banisteriopsis caapi contains the Aspects of Ayahuasca
ß-carboline derivatives harmine, tetrahydroharmine, Ayahuasca is unique in that its pharmacological and harmaline as the major alkaloids (Callaway, et activity is dependent on a synergistic interaction al., 1996). Trace amounts of other ß-carbolines have between the active alkaloids in the plants. One of the also been reported (McKenna, et al., 1984; Rivier & components, the bark of Banisteriopsis caapi, Lindgren, 1972; Hashimoto and Kawanishi, 1975, contains ß-carboline alkaloids, which are potent 1976) as well as the pyrrolidine alkaloids shihunine MAO-A inhibitors; the other component, the leaves and dihydroshihunine (Kawanishi et al. 1982). The of Psychotria viridis or related species, contains the admixture plant, Psychotria viridis, contains a single major alkaloid, N,N-dimethyltryptamine (DMT), dimethyltryptamine (DMT). DMT is not orally while N-methyl tryptamine and methyl-tetrahydro-ß- active when ingested by itself, but can be rendered carboline have been reported as trace constituents orally active in the presence of a peripheral MAO (McKenna, et al., 1984; Rivier & Lindgren, 1972).
inhibitor - and this interaction is the basis of the The admixture plant Psychotria carthagenensis has psychotropic action of ayahuasca tea (McKenna, been reported to contain the same alkaloids (Rivier & Towers, & Abbott, 1984).
Lindgren, 1972) but a subsequent investigation couldnot confirm the presence of DMT in the single 1. Botanical sources of ayahuasca
collection examined (McKenna, et al., 1984). The In a traditional context, Ayahuasca is a beverage concentrations of alkaloids reported in Banisteriopsis prepared by boiling - or soaking - the bark and stems caapi range from 0.05 % dry weight to 1.95 % dry of Banisteriopsis caapi together with various weight; in Psychotria, the concentration of alkaloids admixture plants. The admixture employed most ranged from 0.1 to 0.66 % dry weight (McKenna, et commonly is the Rubiaceous genus Psychotria, al., 1984; Rivier & Lindgren, 1972). Similar ranges (Rubiaceae), particularly P. viridis. The leaves of P. and values were reported by both groups of viridis contains alkaloids which are necessary for the psychoactive effect (see the sections on chemistry and The concentrations of alkaloids in the ayahuasca pharmacology, below). There are also reports beverages are, not surprisingly, several times greater (Schultes, 1972) that other Psychotria species, than in the source plants from which they are especially P. leiocarpa or P. carthaginensis, are used prepared. Based on a quantitative analysis of the instead of P. viridis, but such reports may be due to a major alkaloids in several samples of ayahuasca botanical misidentification; in any case, use of collected on the upper Rio Purús, Rivier & Lindgren Psychotria species other than P. viridis is rare. In (1972) calculated that a 200 ml dose of ayahuasca Northwest Amazon, contained an average of 30 mg of harmine, 10 mg Colombian Putumayo and Ecuador, the leaves of tetrahydroharmine, and 25 mg DMT. Callaway, et Diplopterys cabrerana, a jungle liana in the same al., determined the following concentrations of family as Banisteriopsis, are added to the brew in alkaloids in the hoasca tea utilized in the biomedical lieu of the leaves of Psychotria. The alkaloid present study with the UDV (mg/ml): DMT, 0.24; THH, in Diplopterys, however, is identical to that in the 1.07; harmaline, 0.20; and harmine 1.70. A typical Psychotria admixtures, and pharmacologically, the 100 ml dose of hoasca thus contains in mg: DMT, effect is the same. In Peru, various admixtures in 24; THH, 107; harmaline, 20; harmine, 170.
addition to Psychotria or Dipolopterys are frequently Interestingly, these concentrations are above the added, depending on the magical, medical, or threshold of activity for i.v. administration of DMT religious purposes for which the drug is being (Strassman & Qualls, 1994).
consumed. Although a virtual pharmacopoeia of McKenna et al. (1984) reported somewhat higher admixtures are occasionally added, the most values for the alkaloid content of several samples of Peruvian ayahausca. These investigators calculated Psychotria, which is a constant component of the that a 100 ml dose of these preparations contained a total of 728 mg total alkaloid, of which 467 mg is including tobacco (Nicotiana sp.), Brugmansia sp., harmine, 160 mg is tetrahydroharmine, 41 mg is and Brunfelsia sp. (Schultes, 1972; McKenna, et al., harmaline, and 60 mg is DMT. This is well within 1995). These Solanaceous genera are known to the range of activity for DMT administered i.m.
contain alkaloids, such as nicotine, scopalamine, and (Szara, 1956) or i.v. (Strassman & Qualls, 1994) and atropine, which effect both central and peripheral is also well within the range for harmine to act adrenergic and cholinergic neurotransmission. The effectively as a monoamine oxidase inhibitor (MAOI).
The Heffter Review of Psychedelic Research, Volume 1, 1998 In vitro, these ß-carbolines function as MAOI at form. (McKenna, et al 1984; Schultes, 1972). DMT approximately 10 nM (e.g., harmine's IC50 for MAOI alone is inactive following oral administration at is 1.25 x 10-8 M; cf. McKenna, et al., 1984; doses up to 1000 mg (Shulgin, 1982; Nichols, et al.
Buckholtz & Boggan, 1977). In mice, harmaline 1991). DMT is active by itself following parenteral administered i.p. at 5 mg/kg causes 100% inhibition administration starting at around 25 mg (Szara, 1956; by 2 hours post-injection, the activity falling off Strassman & Qualls, 1994). Because of its oral rapidly thereafter (Udenfriend et al. 1958) This dose corresponds to approximately 375 mg in a 75 kg administration are employed by users. For example, adult, but, based on the measured concentration of synthetic DMT is commonly smoked as the free harmine in the liver, it is likely that one half this base; in this form, the alkaloid volatilizes readily and dose or less would also be effective. The reasons for produces an immediate, intense psychedelic episode the discrepancy in alkaloid concentrations between of short duration (5 -15 min), usually characterized by the samples examined by Rivier & Lindgren (1972) multicolored, rapidly moving visual patterns behind and those examined by McKenna, et al. (1984) are the closed eyelids (Stafford, 1977). The Yanomamo readily explained by the differences in the methods of Indians and other Amazonian tribes prepare a snuff preparation. The method employed in preparing from the sap of various trees in the genus Virola, ayahuasca in Pucallpa, Peru, where the samples which contain large amounts of DMT and the related analyzed by McKenna et al. (1984) were collected, compound, 5-methoxy-DMT, which is also orally results in a much more concentrated brew than the inactive (McKenna, et al. 1985; Schultes and method employed on the upper Rio Purús, the region Hofmann, 1980). The effects of the botanical snuffs which was the source of the samples examined by containing DMT, while not as intense as smoking Rivier & Lindgren. The concentrations and propor- DMT free base, are similarly rapid in onset and of tions of alkaloids can vary significantly in different limited duration [unpublished data]. The ayahuasca batches of ayahuasca, depending on the method of beverage is unique in that it is the only traditionally preparation, as well as the amounts and proportions used psychedelic where the enzyme-inhibiting of the source-plants.
principles in one plant (ß-carbolines) are used to The notion that the ß-carbolines, by themselves, facilitate the oral activity of the psychoactive are hallucinogenic and thus contribute to the overall principles in another plant (DMT). The psychedelic hallucinogenic activity of the ayahuasca beverage, was experience that follows ingestion of ayahuasca differs based on flawed earlier research (Naranjo, 1967) and markedly from the effects of parenterally ingested has been discredited (Callaway, et al., 1997). As DMT; the time of onset is approximately 35-40 MAO inhibitors, ß-carbolines can increase brain minutes after ingestion, and the effects, which are less levels of serotonin, and the primarily sedative effects intense than parenterally administered synthetic of high doses of ß-carbolines are thought to result DMT, last approximately four hours. The subjective from their blockade of serotonin deamination. The effects of ayahuasca include phosphene imagery seen primary action of ß-carbolines in the ayahuasca with the eyes closed, dream-like reveries, and a beverage is their inhibition of peripheral MAO-A, feeling of alertness and stimulation. Peripheral auto- which protects the DMT in the brew from peripheral nomic changes in blood pressure, heart-rate, etc., are degradation and thus renders it orally active. There also less pronounced in ayahuasca than parenteral is some evidence, however, that tetrahydroharmine DMT. In some individuals, transient nausea and (THH), the second most abundant ß-carboline in the episodes of vomiting occur, while others are rarely beverage, acts as a weak 5-HT uptake inhibitor and affected in this respect. When ayahuasca is taken in MAOI. Thus, THH may prolong the half-life of a group setting, vomiting is considered a normal part DMT by blocking its intraneuronal uptake, and of the experience and allowances are made to hence, its inactivation by MAO, localized in accommodate this behavior (Callaway, et al., 1997).
mitochondria within the neuron. On the other hand, The amounts of ß-carbolines present in a typical THH may block serotonin uptake into the neuron, dose of ayahuasca are well above the threshold for resulting in higher levels of 5HT in the synaptic cleft; activity as MAOI. It is likely that the main this 5-HT, in turn, may attenuate the subjective contribution of the ß-carbolines to the acute effects of effects of orally ingested DMT by competing with it ayahuasca results from their action as peripheral at post-synaptic receptor sites (Callaway, et al., MAO inhibitors, rendering DMT orally active. It is worthy of note that ß-carbolines are highly selectiveinhibitors of MAO-A, the form of the enzyme for 3. Pharmacological actions of Ayahuasca and its
which serotonin, and presumably other tryptamines, including DMT, are the preferred substrates The hallucinogenic activity of ayahuascais a (Yasuhara, et al., 1972; Yasuhara, 1974). This function of the peripheral inactivation of MAO by the selectivity of ß-carbolines for MAO-A over MAO-B, ß-carboline alkaloids in the mixture. This action combined with their relatively low affinity for liver prevents the peripheral oxidative deamination of the MAO compared to brain MAO, may explain why primary hallucinogenic reports of hypertensive crises following the ingestion component, rendering it orally active and enabling it of ayahuasca have not been documented. On the to reach its site of action in the CNS in an intact other hand, Suzuki et al. (1981) has reported thatDMT is primarily oxidized by MAO-B; it is McKenna et al., Investigation of ayahuasca possible, therefore, that high concentrations of ß- product of the oxidative metabolism of DMT in rat carbolines, partially inhibit MAO-B as well as MAO- brain homogenates (Barker, et al. 1980).
A; but the greater affinity of tyramine for MAO-B ß-carbolines exert a variety of neurophysiological enables it to compete for binding to the enzyme and and biological effects (McKenna and Towers, 1984).
displace any residual ß-carbolines. This mechanism ß-carboline derivatives are selective, reversible, would explain the lack of any reports of peripheral competitive inhibitors of MAO-A (Buckholtz and autonomic stimulation associated with the ingestion Boggan, 1976, 1977). Other neurophysiological of ayahuasca in combination with foods containing actions of ß-carbolines include competitive inhibition tyramine (Callaway, et al., 1997).
of the uptake of 5-HT, dopamine, epinephrine, and DMT and its derivatives and the ß-carboline norepinephrine into synaptosomes (Buckholtz and derivatives are widespread in the plant kingdom Boggan, 1976; Pähkla, et al., 1997)), inhibition of (Allen & Holmstedt, 1980) and both classes of Na+ dependent membrane ATPases (Canessa, et al.
alkaloids have been detected as 1973), interference with biosynthesis of biogenic metabolites in mammals, including man (Bloom, et amines (Ho, 1977), and vasopressin-like effects on al. 1982; Barker, et al. 1981a; Airaksinen & Kari, sodium and water transport in isolated toad skin (de 1981). Methyl transferases which catalyze the Sousa and Gross, 1978). ß-carboline-3-carboxylate synthesis of DMT, 5-methoxy-DMT, and bufotenine esterified derivatives have been have been characterized in human lung, brain, blood, implicated as possible endogenous ligands for cerebrospinal fluid, liver, and heart, and also in rabbit benzodiazepine receptors (Lippke et al. 1983). ß- lung, toad, mouse, steer, guinea pig, and baboon carboline ligands of these receptors can induce brains, as well as in other tissues in these species epileptiform seizures in rats and in chickens (McKenna & Towers, 1984). Although the homozygous for the epileptic gene (Morin, 1984, occurrence, synthesis, and degradative metabolism of Johnson, et al. 1984); this proconvulsant action can DMT in mammalian systems has been the focus of be blocked by other receptor ligands, including recent scientific investigations (Barker, et al. 1981b).
diazepam and ß-carboline-carboxylate propyl ester Endogenous psychotogens have been suggested as (Morin, 1984, Johnson, et al. 1984). possible etiological factors in schizophrenia and other ß-carbolines also mental disorders, but the evidence remains equivocal activities in addition to their effects on neuro- (Fischman, 1983). The candidacy of DMT as a physiological systems. For instance Hopp and co- possible endogenous psychotogen essentially ended workers found that harmine exhibited significant anti- when experiments showed comparable levels in both trypanosomal activity against Trypanosoma lewisii schizophrenics and normals; at present the possible (Hopp et al., 1976). This finding may explain the neuroregulatory functions of this "psychotomimetic" use of ayahuasca in mestizo ethnomedicine as a prophylactic against malaria and internal parasites Callaway (1988) has presented an interesting (Rodriguez, et al. 1982). Certain ß-carbolines are hypothesis regarding the possible role of endogenous known to exert mutagenic or co-mutagenic effects, DMT and ß-carbolines in regulating sleep cycles and and the mechanism responsible may be related to their interactions with nucleic acids (Umezawa, et al.
ß-carbolines are tricyclic indole alkaloids that are 1978; Hayashi, et al. 1977). The ultra-violet acti- closely related to tryptamines, both biosynthetically vated photocytotoxic and photogenotoxic activity of and pharmacologically. They are readily synthesized some ß-carbolines has also been reported (McKenna by the condensation of indoleamines with aldehydes & Towers 1981; Towers & Abramosky, 1983).
or alpha-keto acids, and their biosynthesis probablyalso proceeds via similar reactions (Callaway et al., Recent Biomedical Investigations of Ayahuasca
1994). ß-carbolines have also been identified in Although achieving some notoriety in North mammalian tissue, including human plasma and American literature through the popular press and the platelets, and rat whole brain, forebrain, arcuate writings of William Burroughs and Allan Ginsberg nucleus, and adrenal glands (Airaksinen and Kari, (Burroughs and Ginsberg, 1963), the psychological 1981). 6-methoxy-tetrahydro-ß-carboline has been and physiological phenomena induced by ayahuasca recently identified as a major constituent of human have received little or no rigorous study. Various pineal gland (Langer et al. 1984). This compound travelers to the Amazon have reported their own first inhibits the high-affinity binding of [3H]-imipramine hand experiences with ayahuasca (Weil, 1980), while to 5-HT receptors in human platelets (Langer et al.
both formal and informal ethnographic narratives have 1984), and also significantly inhibits 5-HT binding excited the public imagination (Lamb, 1971; Luna to type 1 receptors in rat brain; the compound has a and Amaringo, 1991). Interest in the exotic origins low affinity to type 2 receptors, however (Taylor et and effects of ayahuasca have attracted a steady stream al. 1984). 2-methyl-tetrahydro-ß-carboline and of North American tourists, often enticed by articles harman have been detected in human urine following and advertisements in popular and New Age ethanol loading, (Rommelspacher, et al., 1980) and it magazines (Krajick, 1992; Ott, 1993). Concern over has been suggested that endogenous ß-carbolines and possible adverse health effects resulting from the use other amine-aldehyde condensation products may be of ayahuasca by such naive travelers has recently related to the etiology of alcoholism (Rahwan, 1975).
been expressed by a noted authority on Mestizo At least one ß-carboline has been identified as a by- The Heffter Review of Psychedelic Research, Volume 1, 1998 ayahuasca use (Dobkin de Rios, 1994). These Medicine, University of Amazonas Medical School, concerns are in marked contrast to testimonials of Manaus, and the Department of Pharmaceutical improved psychological and moral functioning by the Chemistry, University of Kuopio, Finland. adherents of the syncretic ayahuasca churches in Since this study was the first of its kind, there was virtually no pre-existing data on the objective The individuals who are attracted to the UDV measurement of the physical and psychological effects seem to belong to a slightly more professional socio- of ayahuasca in human subjects. As a result, this economic class than those who join the Santo Daime.
study was in some respects a pilot study; its primary Of the approximately 7000 members of the UDV in objectives were modest, representing an effort to Brazil, perhaps 5 - 10 % are medical professionals, collect a basic body of data, without attempting to among them physicians, psychiatrists, psychologists, relate the findings to either possible detrimental chiropracters, and homeopathic physicians. Most of effects of ayahuasca, or to possible therapeutic effects.
The study had four major objectives: psychologically beneficial aspects of the practice, and • Assessment of Acute Psychological and evince a great interest in the scientific study of Physiological Effects of Hoasca in Human hoasca, including its botany, chemistry, and pharmacology. The medically educated members can • Assessment of Serotonergic Functions in Long- discuss all of these aspects with a sophistication term Users of Hoasca Tea equal to that of any U.S.-trained physician, botanist, • Quantitative or pharmacologist. At the same time they do have a Constituents of Hoasca Teas in Plasma genuine spiritual reverence for the hoasca tea and the • Quantitative experiences it evokes. The UDV places a high value Constituents of Hoasca Teas on the search for scientific truth, and sees no conflict Most of these objectives were achieved, and the between science and religion; most members of the results have been published in various peer-reviewed UDV express a strong interest in learning as much as scientific journals (Grob, et al., 1996; Callaway, et possible about how the tea acts on the body and al., 1994; Callaway, et al., 1996;. Callaway, et al., brain. As a result of this unique circumstance, the 1997). The results are summarized briefly below. UDV presents an ideal context in which to conduct abiomedical investigation of the acute and long-term Assessment of Acute and Long-term Psychological
effects of hoasca. (In the parlance of the UDV, the tea Effects of Hoasca Teas (Grob, et al., 1996)
is sometimes called hoasca, which is a Portguesetransliteration of ayahuasca. The term as used here The subjects in all of the studies consisted of a applies specifically to the tea used within the UDV, group of fifteen healthy, male volunteers, all of whom while ayahuasca is used to denote non-UDV sources had belonged to the UDV for a minimum of ten years, and who ingested hoasca on average of once Due to a fortunate combination of circumstances, every two weeks, in the context of the UDV ritual.
we were invited to conduct such a biomedical None of the subjects actively used tobacco, alcohol, investigation of long-term drinkers of hoasca by the or any drugs other than hoasca. For some Medical Studies section of the UDV (Centro de comparative aspects of the study, a control group of Estudos Medicos). This study, which was conducted fifteen age-matched males was also used; these by an international consortium of scientists from individuals were recruited from among the friends and Brazil, the United States, and Finland, was financed siblings of the volunteer subjects, and like them were through private donations to various non-profit local residents of Manaus having similar diets and sponsoring groups, notably Botanical Dimensions, socio-economic status. None of the control subjects which provided major funding, the Heffter Research were members of the UDV, and none had ever Institute, and MAPS, (Multidisciplinary Association ingested hoasca tea. for Psychedelic Studies). Botanical Dimensions is a The psychological assessments, administered to non-profit organization dedicated to the study and both groups, consisted of structured psychiatric preservation of ethnomedically significant plants, and diagnostic interviews, personality testing, and MAPS and the Heffter Research Institute are non- neuropsychological profit organizations dedicated to the investigation of administered to the UDV hoasca drinkers, but not to the medical and therapeutic uses of psychedelic the hoasca-niave group, included semistructured and agents. The field phase of the study was conducted during the summer of 1993 at one of the oldest UDV phenomenological assessment of the altered state temples, the Nucleo Caupari located in the elicited by hoasca, was quantified using the Amazonian city of Manaus, Brazil. Subsequent Hallucinogen Rating Scale developed by Dr. Rick laboratory investigations took place at the respective Strassman in his work with DMT and psilocybin in academic institutions of some of the principle human subjects (Strassman, et al., 1994).
Psychiatry, Harbor UCLA Medical Center, the differences from the hoasca-naive subjects in the Department of Neurology, University of Miami Tridimensional Personality Questionnaire (TPQ) and School of Medicine, the Department of Psychiatry, the WHO-UCLA Auditory Verbal Learning Test.
University of Rio de Janeiro, Department of Internal The TPQ assesses three general areas of behavior, McKenna et al., Investigation of ayahuasca viz., novelty-seeking, harm avoidance, and reward physical health, and significant improvements in dependence. With respect to novelty-seeking interpersonal, work, and family interactions.
behaviors, UDV members were found to have greaterstoic rigidity vs exploratory excitability, greater Assessment of Serotonergic Functions in Long-
regimentation vs disorderliness, and a trend toward term Users of Hoasca (Callaway, et al., 1994)
greater reflection vs impulsivity; but there was no Another objective of the study was to investigate difference between the groups on the spectrum whether long-term use of hoasca resulted in any between reserve and extravagance. On the harm identifiable "biochemical marker" that was correlated reduction scale, UDV subjects had significantly with hoasca consumption, particularly with respect to greater confidence vs fear of uncertainty, and trends serotonergic functions, since the hoasca alkaloids toward greater gregariousness vs shyness, and greater optimism vs anticipatory worry. No significant neurotransmitter. Ideally, such a study could be differences were found between the two groups in carried out on post-mortem brains of long-term criteria related to reward-dependence.
drinkers in comparison to those of non-drinkers. In The fifteen UDV volunteers and the control this study, this ideal could not be attained due to the subjects were also given the WHO-UCLA Auditory fact that the subjects were still alive and using their Learning Verbal Memory Test. Experimental brains! We settled on looking at serotonin subjects performed significantly better than controls transporter receptors in blood platelets as the next on word recall tests. There was also a trend, though best alternative, using [3H]-citalopram to label the not statistically significant, for the UDV subjects to receptors in binding assays. The up-or down perform better than controls on number of words regulation of peripheral platelet recalled, delayed recall, and words recalled after considered indicative of similar biochemical events occurring in the brain, although there is some The Hallucinogen Rating Scale, developed by controversy about the correlation between platelet Strassman et. al (1994) for the phenomenological receptor changes and changes in CNS receptors assessment of subjects given intravenous doses of medications (Stahl, 1977; Pletscher and Laubscher, DMT, was administered to the UDV volunteers only 1980; Rotman, 1980). However, platelet receptors (since control subjects did not receive the drug). All were deemed suitable for the purposes of our study, as of the clinical clusters on the HRS were in the mild our objective was not to resolve this controversy but end of the spectrum compared to intravenous DMT.
simply to determine if some kind of long-term The clusters for affect, intensity, cognition, and biochemical marker could be identified. Neither did volition, were comparable to an intravenous DMT we postulate any conclusions about the possible dose of 0.1 to 0.2 mg/kg, and the cluster for "adverse" or "beneficial" implications of such a perception was comparable to 0.1 mg/kg intravenous marker, if detected. We conducted the assays on DMT, and the cluster for somatesthesia was less than platelets collected from the same group of 15 the lowest dose of DMT measured by the scale, 0.05 volunteers after they had abstained from consuming the tea for a period of three weeks. We also collected The most striking findings of the psychological platelet specimens from the age-matched controls who assessment came from the structured diagnostic were not hoasca drinkers. We were surprised to find interviews, and the semi-structured open-ended life a significant up-regulation in the density of the story interviews. The Composite International citalopram binding sites in the hoasca drinkers Diagnostic Interview (CIDI) was used for the compared to control subjects. While the hoasca structured diagnostic interview. None of the UDV drinkers had a higher density of receptors, there was subjects had a current psychiatric diagnosis, whereas no change in the affinity of the receptors for the two of the control subjects had an active diagnosis of labelled citalopram. The significance of this finding, alcohol abuse and hypochondriasis. Only one subject if any, is unclear. There is no other pharmacological among the controls had a past psychiatric disorder agent which is known to cause a similar that was no longer present; an alcohol abuse disorder upregulation, although chronic administration of 5- that had remitted two years previously. However, HT uptake inhibitors has been reported to decrease prior to membership in the UDV, eleven of the UDV both Bmax (the density of binding sites) and 5-HT subjects had diagnoses of alcohol abuse disorders, transporter RNA in rats (Hrinda 1987; Lesch et al., two had had past major depressive disorders, four had 1993). Increases in Bmax for the uptake site in human platelets have been correlated with old age amphetamines), eleven were addicted to tobacco, and (Marazziti et al, 1989) and also the dark phase of the three had past phobic anxiety disorders. Five of the circadian cycle in rabbits (Rocca et al., 1989). It has subjects with a history of alcoholism also had been speculated (Marazziti et al, 1989) that histories of violent behavior associated with binge upregulation of 5-HT uptake sites in the aged may be drinking. All of these pathological diagnoses had related to the natural course of neuronal decline.
remitted following entry into the UDV. All of the Although our sample size was limited, we found no UDV subjects interviewed reported the subjective correlation with age, and the mean age of the sample impression that their use of hoasca tea within the was 38 years. Also, none of our subjects showed context of the UDV had led to improved mental and evidence of any neurological or psychiatric deficit. In The Heffter Review of Psychedelic Research, Volume 1, 1998 fact, in view of their exceptionally healthy point measurements were discontinued. Breaths per psychological profiles, one of the investigators minute fluctuated throughout the 240 minutes, from a speculated that perhaps the serotonergic upregulation low of 18.5 at baseline to a high of 23 breaths per is associated, not simply with age, but with minute at 100 minutes. Temperature rose from a "wisdom" -- a characteristic often found in the aged, baseline low of 37 ° C at baseline to a high of 37.3 and in many hoasca drinkers.
°C at 240 min (although the ambient temperature Another interesting self-experiment related to this also increased comparably during the course of the finding was carried out by one of the investigators, experiments, which were conducted from 10:00 - Jace Callaway, following his return to Finland after 16:00). Heart rate increased from 71.9 bpm at the field phase of the study was completed. Dr.
baseline to a maximum of 79.3 bpm by 20 minutes, Callaway has access to Single Photon Emission decreased to 64.5 bpm by 120 minutes, then Computerized Tomography gradually returned toward basal levels by 240 facilities in the Department of Pharmacology at the minutes. There was a concomitant increase in blood University of Kuopio. Suspecting that the causative pressure; both systolic and diastolic pressure agent of the unexpected upregulation might be increased to maxima at 40 minutes (137.3 and 92.0 tetrahydroharmine (THH), mm Hg respectively) over baseline values (126.3 and SPECT scans of his own brain 5-HT uptake receptors 82.7 mm Hg respectively) and returned to basal prior to beginning a six week course of daily dosing values by 180 minutes. We also measured with tetrahydroharmine, repeating the scan after the nueroendocrine response for plasma treatment period. He did indeed find that the density cortisol, and grwoth hormone; all showed a rapid and of central 5-HT receptors in the prefrontal cortex had dramatic increases over basal values from 60 minutes increased; when he discontinued THH, their density (cortisol) to 90 minutes (growth hormone) to 120 gradually returned to previous levels over the course minutes (prolactin) after ingestion. The observed of several weeks. While this experiment only had response, typical of serotonergic agonists, are one subject, if it is indicative of a general effect of comparable to the values reported by Strassman & THH that can be replicated and confirmed, the Qualls (1994) in response to injected DMT. In our implications are potentially significant. A severe study, however, the response to oral DMT was deficit of 5-HT uptake sites in the frontal cortex has delayed by a factor of four or five. Dr. Russell been found to be correlated with aggressive disorders Poland, of the Harbor-UCLA Medical Center, carried in violent alcoholics; if THH is able to specifically out the neuroendocrine measurements. reverse this deficit, it may have applications in thetreatment of this syndrome. These findings are Characterization of the Pharmacokinetics of
especially interesting when viewed in the context of Hoasca Alkaloids in Human Subjects (Callaway,
the psychological data collected in the hoasca study et al., 1996; 1997)
(Grob, et al., 1996). The majority of the subjects The fourth objective of the study was to measure had had a previous history of alcoholism, and many pharmacokinetic parameters of the hoasca alkaloids in had displayed violent behavior in the years prior to plasma following ingestion of hoasca tea, and to joining the UDV; virtually all attributed their correlate this to the amounts of alkaloids ingested.
recovery and change in behavior to their use of hoasca The UDV collaborators held a special "preparo" to tea in the UDV rituals. While it can be argued that prepare the sample of hoasca that was used for all their reformation was due to the supportive social and subjects in the study. The mestres confirmed the psychological environment found within the UDV, activity in the usual manner, via ingestion, and the finding of this long-term change in precisely the pronounced it active and suitable for use in the study.
serotonin system that is deficient in violent Subsequent analysis by HPLC found the tea to alcoholism, argues that biochemical factors may also contain, in mg/ml: harmine, 1.7; harmaline, 0.2; THH, 1.07; and DMT 0.24. Each subject receivedan aliquot of tea equivalent to 2 ml/kg body weight, Assessment of the Acute Physiological Effects of
which was consumed in a single draught. Based on Hoasca Tea (Callaway, et al., 1997)
the average body weight (74.2 ± 11.3 kg), the average The major focus of the biochemical and dose of tea was 148.4 ± 22.6 ml, containing an physiological measurements carried out for the study average of 35.5 mg DMT, 158.8 mg THH, 29.7 mg was on the acute effects subsequent to consuming harmaline, and 252.3 mg harmine. These doses are hoasca tea. One of the objectives was simply to above the threshold level of activity for DMT as a effects of hoasca psychedelic, and for harmine and THH as MAO physiological functions, such as heart rate, blood inhibitors; harmaline is essentially a trace constituent pressure, and pupillary diameter, subsequent to of hoasca tea (Callaway, et al., 1996, 1997).
ingestion. We found that all of these responses were Only 12 of the 15 volunteers had sufficient well within normal parameters. Hoasca, not plasma levels of DMT to permit pharmacokinetic surprisingly, caused an increase in pupillary diameter measurements, possibly due to early emesis during from baseline (pre-dose) levels of 3.7 mm to the course of the session. Of these, the maximum approximately 4.7 mm at 40 minutes, which plasma concentration (Cmax) (15.8 ng/ml) occurred continued to 240 minutes after ingestion at which at 107 minutes after ingestion, while the half-life (T1/2 McKenna et al., Investigation of ayahuasca was 259 minutes. THH was measured in 14 of the suggest themselves for future research, the following 15 subjects; the Cmax was 91 ng/ml, reached at 174 min. This compound displayed a prolonged half-life • Effect of hoasca on women, particularly
of 532 minutes, in contrast to harmine which had a pregnant and/or lactating women. For
half-life of 115.6 min. The Cmax for harmine and simplicity's sake, our initial study included only harmaline was 114.8 and 6.3 ng/ml, respectively, and male subjects who had imbibed the tea on a time of maximum concentration (Tmax) was 102 and regular basis for at least ten years. Thus our 145 minutes, respectively. The T1/2 for harmaline sample was deliberately restricted; it included could not be measured (Callaway, et al.,1997).
only experienced hoasca drinkers, and only men, In many ways this study was conceived because just to minimize the number of variables. But of the need to collect some basic data on the women also drink hoasca, and moreover, most physiological and pharmacokinetic characteristics of do so throughout pregnancy and lactation; ayahuasca, since none had previously existed. The indeed, children in the UDV are baptized with a conclusions to be drawn from the results, if any, are tiny spoonful of hoasca, although they are not interesting and potentially significant, particularly in usually exposed to pharmacologically active that these findings may offer a physiological rationale amounts until at least age 13. There are many for the marked improvements in psychological health issues here worthy of study. For example, that is correlated with long-term hoasca use. Not women claim that hoasca has positive benefits surprisingly, the highest plasma concentrations of both in managing their pregnancy, and in DMT correlated with the most intense subjective assisting birth; many will take hoasca during effects; however, the psychological measurement labor to facilitate the process. The role of hoasca during pregnancy and lactation, whether adverse comparable plasma levels of injected DMT in the or positive, is just one of a score of questions study by Strassman & Qualls (1994) gave effects that which could be answered by follow-up studies were more intense than those reported from the hoasca using women hoasca drinkers.
tea. One possible explanation is that THH, by acting • Prospective studies, with children and new
as a 5-HT reuptake inhibitor, may have resulted in a members. For similar reasons, our study did
greater availability of 5-HT at the synapse, and this not include any recent converts to the UDV, nor may have competed with DMT for occupancy at any children, who, if they choose, are allowed to attend UDV sessions and imbibe smaller Another point worthy of remark is that the amounts of hoasca as early as age 13. Nor did activity of THH in hoasca is apparently more a the study include any recent adult converts to the function of its inhibition of 5-HT uptake than to its UDV. Clearly, prospective studies of both action as an MAOI. THH is a poor MAOI compared groups could add a great deal to our knowledge.
to harmine (EC50 = 1.4 x 10-5 M vs 8 x 10-8 M for In view of our finding that hoasca apparently harmine), and while the plasma levels for harmine are brings about long-term increases in serotonin well above the EC50 values, those for THH are well uptake receptor densities, the implications of this below the EC50 value for this compound as an MAOI.
need to be further investigated, and prospectivestudies may clarify this question. For instance, is the increase in serotonin uptake sites a The major objectives of the initial biomedical consequence of regular imbibition of hoasca, as investigation of hoasca have been met, including the would seem the obvious conclusion, or are overall objective, that of developing a basic body of hoasca drinkers as a group biased toward those descriptive information on the physiological and who are predisposed toward naturally high psychopharmacological characteristics of the tea.
receptor densities? And But, like all good science, these investigations raise implications of either finding? more question than they have answered. It seems questions, as well as a host of sociological and clear that ayahuasca is relatively safe; it can be taken developmental questions, could be addressed in a on a regular schedule for months or even years prospective study of children of UDV members without producing any adverse effect. Indeed, all of who remain in the group and start to imbibe our subjects were highly functional individuals who hoasca regularly in adolescence. An obvious attribute much of their "coping" skills to the tea and question to answer in this context would be an the lessons it has taught them, albeit within the assessment of children and adolescents who were doctrinal context of the UDV. None of them showed exposed to hoasca in utero, to determine the any signs of physical disease, or neurological or impact, if any, of prenatal hoasca exposure on psychological deficits, indeed, many had higher their subsequent neurological and psychological scores in some of the psychometric testing regimes development. Another question germane to the than comparable control subjects who had never possible long-term health benefits of regular imbibed hoasca. Yet many questions remain, and it hoasca use is that of whether the practice might is to be hoped that future investigations will be done, prove to be prophylactic against alcohol and drug and that some of the most relevant questions will be abuse for adolescents who consume the tea at least partially answered. Among areas which within the UDV structure.
The Heffter Review of Psychedelic Research, Volume 1, 1998 • Brain imaging and electrophysiological
Now, the process that has unfolded in Western studies To the degree that facilities can be made
culture since Richard Spruce first reported on available, brain imaging and electrophysiological ayahuasca use among the Indians of the Norwthwest studies of the acute and chronic effects of hoasca Amazon in 1855 (Anon, 1855; Spruce, 1873) has would further fill in the picture of its reached a new stage. Ayahuasca has emerged from the Amazonian jungles where it has remained cloaked • Therapeutic applications of hoasca in
in obscurity for thousands of years, to become the treatment of substance abuse and alcoholism
sacramental vehicle for new syncretic religious The experience of UDV members, recounted in movements that are now diffusing from their center of the structured "life-story" interviews, would origin in Brazil to Europe, the United States, and seem to indicate that hoasca has real potential as throughout the world. As the world observes this a therapeutic agent in treating substance abuse process unfolding (with joyous anticipation for some, and with considerable trepidation for others), the psychopathologies. Most of the subjects inter- focus for the scientific study and understanding of viewed were involved with substance abuse prior ayahuasca has shifted from the ethnographer's field to joining the UDV, and have since ceased.
notes and the ethnobotanist's herbarium specimens, Most attribute their recovery to the tea; it would to the neurophysiologist's laboratory and the seem that confirmation of their experience and psychiatrist's examining room. With the completion further information could be collected relatively of the first detailed biomedical investigation of easily, perhaps through a prospective study using ayahuasca, science now has the basic corpus of data recent converts to the UDV having prior needed to ask further questions, regarding the involvement with substance abuse or other pharmacological actions, the toxicities and possible dangers, and the considerable potential Ayahuasca has • Immunomodulatory effects of hoasca
to heal the human mind, body, and spirit.
Another parameter that could be easily assessed, Humanity's relationship with ayahuasca is a long- that may have important implications for the term commitment, expressed on an evolutionary time long-term health effects of hoasca, is the question scale, that has already taught us much, and from of its possible effects on the immune system.
which we can still learn much, provided we have the Hoasca may be an immunostimulant, and thus courage, and the tools, to ask the right questions.
potentially beneficial in maintaining resistance todisease; on the other hand, it could be animmunosuppressant, and this would also haveserious implications for long-term or frequentuse. Although hoasca tea is customarily used asa ritual sacrament rather than a medicine,anecdotal reports suggesting that hoasca mayfacilitate recovery from serious illnesses such ascancer, and well-designed studies are needed toinvestigate this question. One possibility is thatdiscontinuation of the use of alcohol, tobacco,and drugs of abuse, as is common in UDVmembers, may contribute to long-term salutaryeffects on health. Ayahuasca, or hoasca, whether known by these names, or any of numerous other designations, haslong been a subject of fascination to ethnographers,botanists, psychopharmacologists, and others with aninterest in the many facets of the human relationshipwith, and use of, psychoactive plants. With itscomplex botanical, chemical, and pharmacologicalcharacteristics, and its position of prime importancein the ethnomedical and magico-religious practices ofindigenous Amazonian peoples, the investigation ofayahuasca in its many aspects has been an impetus tothe furtherence of our scientific understanding of thebrain/mind interface, and of the role that psychoactiveplant alkaloids have played, and continue to play, inthe quest of the human spirit to discover and tounderstand its own trancendent nature.
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