Drug info - A Scientist Reflects on the Discovery and Future of LSD

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Dr. David Nichols of Purdue University is a longtime researcher on the chemistry of psychedelic drugs. Note that this essay was not written in response to Dr. Albert Hofmann's passing last week, but was instead written a few years ago to mark the 50th anniversary of the discovery of LSD.

BTW, Dr. Nichols is responsible for coining the term "entactogen".

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A Scientist Reflects on the Discovery and Future of LSD

by

David E. Nichols, Ph.D.

I first met Albert Hofmann in 1975 when he came to Purdue University to deliver a lecture. I was a young assistant professor, and considered it a great honor to meet Dr. Hofmann, and especially to have the opportunity to have informal discussions with him. Over lunch with the faculty, he related that he had done his doctoral work on the structure of chitin, the substance of lobster shells and insect bodies (interested persons can find the publication of Dr. Hofmann's doctoral work in Helvetica Chimica Acta, volume 12, pp 616-637, 1929). I've often wondered how many people think of Albert Hofmann when they see a lobster; not many, I would guess!

Later on, Dr. Hofmann delighted us with his descriptions of the isolation of psilocybin from an extract of psilocybe mexicana mushrooms. He related that the final separation and identification of the active principle was accomplished by paper chromatography, where he and several colleagues ate paper sections cut from the chromatogram, each of which contained one of the separated components of the mushrooms. This no doubt was the first (and perhaps only?) example of "blotter psilocybin." These stories were the stuff of legends to me!

The world is now a vastly different place than it was on the afternoon of April 19, 1943, when Albert Hofmann did what, at that time, seemed a perfectly natural thing to do and carried out a self-experiment with 0.25 mg of a semisynthetic ergot derivative that he had first prepared in 1938. In carrying on this tradition of self-experimentation, he could not have imagined that a little more than two decades later such experimentation would be considered reprehensible conduct, and that eventually it would be considered, at least in one major country, criminal behavior of the most serious kind.

I am curious to know how Dr. Hofmann feels today about his discovery of LSD. Few would deny that the discovery of LSD has had a major impact on art, music, religion, and Western culture in general. Furthermore, it has served as a catalyst to help revitalize neuroscience; the earliest study to differentiate between types of serotonin receptors in the brain used LSD as a research tool, showing that it had affinity for two distinct types of serotonin binding sites. Today we know that LSD has high affinities for at least eight of the fifteen different subtypes of serotonin receptors that have now been characterized by neuroscientists. The fact that no other brain neurotransmitter has so many different types of receptors suggests that serotonin may be phylogenetically the oldest monoamine neurotransmitter. We also now know that LSD has a high affinity for other brain receptor sites, including alpha-2- adrenergic receptors, and dopamine D1 and D2 receptors. Neuroscientists have not begun to touch on the physiological implications of all this information, even though thousands of scientific papers have been published from studies that employed LSD in some way.

The recent marriage of molecular biology and neuroscience has resulted in a wealth of new information on transmitter and receptor systems that may be relevant to the action of LSD and other psychedelic agents. Furthermore, the importance of serotonin in normal brain function is only now being appreciated, as we discover that serotonin uptake inhibitors such as fluoxetine (Prozac), sertraline (Zoloft), and others are effective in treating depression, anxiety, panic disorder, and obsessive-compulsive disorder. A drug which acts as a stimulant at one subtype of serotonin receptor can abort migraine headaches, while a drug that blocks a different subtype of serotonin receptor can prevent the severe nausea that accompanies cancer chemotherapy. Another type of serotonin receptor stimulant is useful in treating anxiety, while yet another holds promise for treating hypertension. New therapeutic agents based on our increased understanding of serotonin function are only now being introduced into medicine and it is clear that the trend will continue. While no one would suggest that LSD will be useful as a tool to study every aspect of serotonin function, the fact remains that it has been an important fundamental tool and catalyst in helping to understand the roles that serotonin plays in the brain. Certainly it was one of the significant players in the very early stages of the neuroscience revolution that is presently in full bloom.

Nevertheless, even before one could appreciate the importance of LSD as a basic tool for pharmacologists to study neurophysiology, it was clear that LSD had profound effects on what we call the mind. It is this important property of LSD that has been neglected by researchers for so long. For my own part, I believe that LSD, or drugs like it, will one day in the future be a mainstay of research on the mind. I also believe that these drugs have the potential to be useful in treating a variety of psychiatric disorders, but that we as a society presently lack the technology and knowledge base to employ them effectively. Perhaps Dr. Hofmann also shares these beliefs, yet how discouraging it must be for him to know that he will not see this research carried out in his lifetime. How does one feel about a discovery that seems so profound and so full of promise, but which through no fault of one's own, somehow goes awry? For Albert Hofmann there must be more. To leave it as it is would be like discovering penicillin, having a bottle full on the shelf, and watching people dying of infections all around you because physicians were afraid to try your new medicine. One of my personal fears is that the potential of these drugs may not be realized even in my own lifetime.

Although I have not carried out studies with psychedelic drugs in humans my laboratory is one of only a very few in the world where students can come to pursue Ph.D. training with a project that might involve the study of psychedelic agents. Perhaps my laboratory is indeed, as one of my former students described it, "an oasis in the midwest." Since 1969 I have continuously carried on research with psychedelic drugs. My research has essentially focused on the medicinal chemistry and pharmacology of these agents; why certain features of psychoactive molecules produce their specific physiological effects. Although these studies are carried out in rats rather than humans, we nevertheless know a lot more about how these drugs work than we otherwise would. In particular, we now understand a good deal about the chemical nature of psychedelic molecules and the brain receptors to which they bind. My laboratory has studied a large variety of mescaline analogs, substituted amphetamine analogs, and various tryptamines related to psilocin. More recently we have uncovered new data about the importance of some of the structural features of lysergic acid amides related to LSD. We have even shown that there are a few LSD analogues with potency surpassing that of LSD itself (e.g compounds we named ethlad and allylad)! These are only a few of the different kinds of studies that have taken place in my laboratory since 1969. They lie in the realm of what is called basic science and are seldom topics for conversation over dinner. Yet, I look at these studies as long-term investments; the immediate value of some of them may not be apparent, but I believe they will ultimately provide an important foundation for future research.

When I wrote my Ph.D. thesis in 1973 we in the scientific community had to call these drugs psychotomimetics. I have watched while this term, which was inaccurate as a scientific label, has gradually been replaced by the more neutral term hallucinogen. More recently, both the 7th and 8th editions of Goodman and Gilman's The Pharmacological Basis of Therapeutics ("the pharmacologist's Bible") have indicated that it is appropriate to use the term psychedelic in the scientific literature. This may seem like a trivial point to many people, but in the hard-nosed community of scientists, it represents a real but subtle change. Nevertheless, I have not yet seen a publication in a scientific journal that used the word psychedelic.

What would I tell Dr. Hofmann if I could speak with him face to face today that would be any different from the thousands of testimonials he must already have received? Perhaps the thoughts I share with him today should be those of a research scientist who is still working to bring about a time when his research will be funded by the National Institute of Mental Health rather than the National Institute on Drug Abuse. In that role, I believe that I can offer some hope that one day his discovery will be recognized for what it is. Despite the enthusiasm that many people feel over possible changes in attitude in governmental administration, I do not believe this recognition will occur either quickly or painlessly. But change must occur.

Although mainstream science ignores the potential value of LSD, it seems to me that the baby has been thrown out with the bath water. The reasons for this are many, but in fact media sensationalism and the portrayal of LSD as such a dangerous drug has colored even scientists' views. I recall a plane trip I took several years ago where I was seated next to a physician who had just completed his residency in psychiatry. In describing my own interests he was surprised to find that anyone was still pursuing research on psychedelic drugs. I indicated to him quite matter of factly that LSD had indeed proven useful in certain, well- designed clinical studies whereupon he exclaimed with some surprise, "You mean they actually gave LSD to humans?" I was appalled that even within the medical profession, education had not been an equal to media sensationalism.

Make no mistake--scientists are objective only when they want to be. There are important members of the scientific community today who would encourage research on the physiological changes produced by LSD, but who abhor any mention of the use of LSD to study the mind, or the possibility that it might be useful in psychiatric practice. To a large extent their position has been hardened by advocates for the use of LSD as a tool for "spiritual growth" or for "personal development." However, in dismissing any possible value of LSD in the psychiatric or therapeutic context, they also allow the results of poorly designed research protocols and inept investigators of the past to color their vision of the future. How can we reasonably expect legislators or government officials to be any more well informed?

It is probably also important to note that studies using low doses of LSD (psycholytic therapy) comprise the majority of the reports in the scientific literature. It is these studies, which seemed least successful in terms of long-term therapeutic benefit, that are most often cited by critics when they wish to negate the therapeutic value of LSD. By contrast, the most promising therapeutic results seemed to be obtained using high doses of LSD (psychedelic therapy). Indeed, therapeutic improvement was quite dramatic in some of these cases, and evident even to those lacking clinical training. Unfortunately, there are fewer reports of the latter method in the literature because it was less reproducible and more controversial. Hence, consensus on the clinical value of LSD was heavily weighted by large numbers of reports from studies with questionable success. Rather than trying to separate the signal from the noise, critics simply dismissed the whole approach as lacking any value.

It would be impossible for me to name all the mainstream scientists that I have met over the past 25 years, whether psychologists, cognitive scientists, linguists, physicians, or neuroscientists of all shades, who have expressed frustration at not being able to use LSD in their own research. Not just because there are, in fact, more legal difficulties in obtaining and working with it, but more importantly because there are no federal funding priorities and there is simply no place for them to do the research. There are no research institutes, no pharmaceutical companies, and few academic appointments where this work can presently be pursued. However, I am convinced that the scientific manpower and creative talent will be available whenever an avenue for this work is ultimately reopened.

What are our starting points for the future? I have maintained for years that the best hope for using LSD in research lies with the medical profession. Even today, LSD can still be used by trained clinical research scientists with well designed experimental protocols. There will be many readers who would argue strenuously that LSD should be available to a wider group of "researchers," including counselors, therapists of all kinds, shamanic healers, and the like. There is a strong desire on the part of many individuals to use LSD for personal development, or "spiritual growth." Albert Hofmann himself could probably be counted as a proponent of the latter. It is not the place of a scientist to say whether or not these are legitimate goals of LSD use. Rather, I shall propose my view of how best to bring LSD back into medicine and psychiatry. I do believe that any general and widespread use of LSD would be detrimental to that effort.

Therefore, the following arguments are mainly directed toward identifying uses for LSD that will be defensible to grant reviewing agencies, where it might be expected that enough useful "hard" data could be obtained to justify further experimentation and methods development. I am absolutely convinced that our best hope for success in exploring the potential of LSD lies in working within the context of currently-accepted scientific research methodology. This is a long-term plan that would build a substantial foundation of scientific fact upon which more sophisticated and exotic hypotheses could later be built. Although this is a conservative position, and progress may be slow, there have already been advances in this direction within the past few years. More importantly, this is the approach that government agencies and oversight committees recognize, and that leads to acceptance of results by the scientific community as a whole.

In my mind there are several well-documented areas suitable for research that have been overlooked or abandoned by the scientific community. Most of these are well known to readers familiar with the psychedelic literature. For example, it seems there is little doubt that the treatment of terminal cancer patients with LSD by Dr. Albert Kurland and his associates at the Spring Grove State Hospital was quite effective. Need for narcotic analgesics was often reduced, depression and anxiety decreased, and in general the quality of life was improved as these patients approached death; indeed the NIMH had recognized this as a legitimate use for LSD. The ultimate fact of our mortality is with us continually. How can a drug that might help us come to terms with that eventuality be neglected for much longer? Although this is an area where traditional Western religious beliefs may present obstacles to acceptance of this type of therapy, the focus of medicine should be on the alleviation of suffering. The reduction of pain and the improvement of mood in terminal patients are legitimate goals, however achieved, and the Calvinist-based notion that suffering is our lot in life is not compatible with good medical practice.

The comprehensive and detailed studies by Barr and Langs (LSD: Personality and Experience, Wiley-Interscience, New York, 1972) demonstrated in an unambiguous way that the personality of the subject plays an enormous and critical role in determining the effect, both qualitatively and quantitatively, of LSD. The phenomena could not be explained or understood from a purely pharmacological perspective. These same researchers demonstrated that in some individuals LSD can have predominantly positive effects, in spite of the fact that their studies were not well designed to detect them. They reached a conclusion familiar to most LSD researchers that the drug works, at least in part, by releasing pre-existing behavioral, affective, and cognitive patterns. In the preface to their book they noted, "We hope that this book will serve as firm evidence of the value of LSD as an investigative instrument, and that it may help lead to a reconsideration of the use of psychedelic drugs for scientific inquiry." How can psychology, especially the areas of cognitive science and personality theory, continue to ignore the fact that LSD reveals properties of the mind that are, under ordinary circumstances, difficult if not impossible to measure?

Another intriguing area for research is the "near death experience" (NDE), which is now quite well documented. This phenomenon can occur when someone experiences clinical death but is later resuscitated. In typical accounts of an NDE, patients may report traveling through a long dark tunnel and then emerging into light, or meeting a being of light. They often sense the presence of, or may see, heavenly messengers and may have visions of a beautiful existence that lies beyond death. Loved ones who have already died may appear and comfort the patient with reassurance that death is not to be feared; that they eagerly await the arrival of the person who is dying. Inevitably, the NDE patient is told, or simply knows that it is time to "go back." Typically, the latter is the last memory of the NDE experience prior to resuscitation. While there is disagreement as to whether this phenomenon represents a true vision of the afterlife or is simply a remarkable hallucination, no one disputes the fact that NDEs can profoundly change the life of the person who has had one. NDE-induced personality changes are invariably beneficial, including improved mood, increased self- confidence and self-esteem, and reduced fear of death and dying. The similarities between NDEs, LSD-induced "peak experiences" and the spontaneous peak experiences described by Abraham Maslow are so great that the only reasonable conclusion is that they involve similar neurochemical mechanisms in the brain. Those who consider this perspective too reductionistic can view neurochemical changes as effect, rather than cause, without altering the basic premise.

Here we might note the Ph.D. work of Walter Pahnke, which drew convincing parallels between psilocybin-induced effects and spontaneous mystical experience. Perhaps mention of these studies will cause some theologians to wince, but I have never heard any criticism of his experimental methodology. It is hard to understand why psychiatry, searching for real cures instead of palliatives, has failed to use the paradigm of the NDE/peak experience to develop new treatments for a variety of emotional problems. And, as Dr. Stanislav Grof has commented, what benefits might occur in individuals who are already highly "self actualized?"

Another promising area of research may lie in the rehabilitation of criminals. We hear, almost on a daily basis, how crowded the prisons are; that we need to build more of them. This whole approach to "justice" seems to be getting out of hand. Perhaps there is a need to return to the idea that some individuals can be rehabilitated, but to address new means by which this could actually be accomplished. How many officials in law enforcement today are aware that Dr. Timothy Leary's work with prisoners, using psilocybin, produced some very dramatic recoveries? The successes in that pilot program seem to have resulted primarily from drug-induced peak experiences, the effects of which were just noted above. It seems difficult for me to believe that we, as a society, will not at some future point accept the premise that there are effective methods of rehabilitating criminals so that they no longer pose a threat to society. Leary's pilot study seems to suggest one possibility that desperately calls out for replication and further research.

An area where very little research has been done is on the relationship between dreaming and the LSD experience. An early study in two sleeping subjects by Clara Torda showed that very low doses of LSD immediately brought on episodes of REM, a stage of the sleep cycle that is characterized by rapid eye movements and is associated with dreaming. Were these ordinary dreams, or did they have unusual characteristics? In particular, were they lucid dreams, which have been compared to certain states induced by LSD? This would seem to be a fascinating study to repeat but with an expanded research design, not just to learn what kinds of dreams LSD provokes, but for studying the neurochemical substrates of the dreaming process itself. No scientist will deny that the phenomenon of dreaming, which is common to all mammals, is an intriguing subject. Why we dream is not only a recurring theme in literature and art, but has been, and should continue to be, an important realm of scientific research. However, tools to study the process are sadly lacking. If LSD can give us insight into the dreaming process, why isn't it being used? Again, in time, I believe this approach will be re- examined.

An area where almost no solid research has been published involves the use of LSD in cognitive and perceptual psychology. LSD clearly alters various aspects of cognition and perception, and sophisticated methodology now exists to measure these changes. Most of these kinds of studies were not even approachable with the knowledge base and experimental paradigms of twenty and thirty years ago. The ways in which LSD and similar drugs change these processes may well give insight into the mechanisms of normal cognitive processes, and may suggest ways that these processes are changed under a variety of environmental or pathological stressors. Coupling this approach with some of the new brain imaging tools now available such as magnetic resonance imaging (MRI) and positron emission tomography (PET) would seem to offer extremely powerful tools in the study of brain function.

These seem to me to be a few legitimate areas for research with LSD which have already been identified. While in some cases these studies touch on areas that are culturally sensitive, straightforward questions can be asked and answered. Whether or not someone returns to prison is easily determined. The terminal patient's reduced need for analgesics, or improvement in objective measures of mood or self-esteem in other patients following the use of LSD in a well designed and executed experimental protocol will be proof for the efficacy of these approaches.

Many influential people have made public pronouncements about the dangers and lack of value of research with LSD and related drugs. These individuals will eventually retire from public life and relinquish their power and we must hope that more enlightened and progressive persons will take their place. We also desperately need a greater number of individuals to pursue Ph.D. and M.D. degrees who believe that this research is worthwhile, and who are willing to devote some portion of their effort to bringing about change. The number of well-trained researchers actively pursuing this line of inquiry in the United States can now be counted on one hand. Many people decry the lack of research, but few are willing to make a contribution.

In spite of these obstacles, I am confident that ultimately the value of psychedelic drugs as tools to study the mind will be realized. Those of us who believe in this possibility must put aside the difficulties that presently face researchers in this field, and must work to bring the future nearer. I tell my own students that long after we have found a cure for cancer, have understood the aging process, and have conquered most other serious human illnesses, we will still be trying to understand the mind. I see this as an enduring quest that will remain for all time. I do not believe that as a species we will ever truly comprehend the human mind in all of its wondrous complexity.

To ask who we are and why we are here is to follow a tradition as old as mankind itself; these represent ultimate questions for our species. There is no reason to assume that the pursuit of answers to these questions will ever be outdated or out of fashion. Any method that brings us closer to answers must, by definition, be deemed highly important. We must not ignore the value of psychedelic drugs in this quest, casually relegating them to some "drugs of abuse" trash bin.

Although many believe that reductionistic science is particularly unsuited for this pursuit, that a "new paradigm" is required, in the grand scheme of things it seems of little consequence to me what paradigm is used; none will offer up definitive solutions at any time in the near future. It is in a larger context that I see a sensible and responsible society of the future finally acknowledging the importance and the value of LSD as a catalyst in bringing our resources to bear on the study of the mind.

Congratulations on the 50th anniversary of the discovery of LSD, Dr. Hofmann. Although it was a difficult delivery, I believe that your problem child may be nearing adolescence!

Reputation Comments on this post:

great speculative article laced with examples