HerbalEGram: Volume 15, Issue 9, September 2018

By Dennis J. McKenna, PhD
Director of Ethnopharmacology, Heffter Research Institute

Editor’s note: A previous version of this article was published as the first chapter of the new book Ethnopharmacologic Search for Psychoactive Drugs (Synergetic Press, 2018),¹ a volume of essays based on presentations made at the Ethnopharmacologic Search for Psychoactive Drugs symposium in Buckinghamshire, England, in June 2017. This symposium was the 50th anniversary commemoration of the first Ethnopharmacologic Search for Psychoactive Drugs symposium held in 1967 in San Francisco under the sponsorship of the US National Institute of Mental Health. Present at the initial conference were some of the leading pioneering researchers who initiated much of the modern chemical, ethnopharmacological, and ethnobotanical investigations of various plants and non-botanical materials with known psychoactive uses in native cultures.

The First Ethnopharmacologic Search for Psychoactive Drugs Symposium (San Francisco, 1967)

In 1967, a landmark symposium in the history of psychedelics was held in San Francisco, California, under the sponsorship of the US National Institute of Mental Health (NIMH), which was part of the US Department of Health, Education, and Welfare (now called the US Department of Health and Human Services [HHS]). The title of the invitational symposium was “Ethnopharmacologic Search for Psychoactive Drugs” (ESPD), and a volume of the proceedings was published under the same name later that year and sold through the US Government Printing Office (now called the US Government Publishing Office [GPO]). The volume, now out of print, has become a classic reference in the ethnobotanical literature.

This was probably the first time that an interdisciplinary group of specialists, ranging from ethnobotanists to neuroscientists, gathered in one place to share their findings on a topic of widespread interest at the time: the use of psychoactive plants in the context of indigenous and non-Western societies. In 1967, the word “psychedelic” had not yet become stigmatized. (According to the National Institute of Drug Abuse, a psychedelic is a substance that “distorts perception, thought, and feeling.” A psychoactive substance is defined more generally as a substance that has a “specific effect on the brain.”²) There were still expectations in the psychiatric and neuroscientific communities that these little-known and curious agents, used for centuries in the ethnomedicine and rituals of traditional cultures, might yield new healing substances that could be used in our own troubled society, and serve as important tools for exploring the human mind.

The roster of attendees at the 1967 symposium reads like a Who’s Who of ethnopharmacology: John Daly, PhD; Daniel Efron, MD, PhD; Daniel X. Freedman, MD; Bo Holmstedt, MD, PhD; Nathan Kline, MD; Richard Schultes, PhD; Alexander Shulgin, PhD; Stephen Szára, MD; R. Gordon Wasson; Andrew Weil, PhD; and many others. Only a few of the researchers who attended the original symposium are still alive, and, of those, even fewer remain active in the field. Their work contributed to making the first ESPD symposium one of the most unusual and interdisciplinary scientific convocations ever organized.

Originally, follow-up symposia were planned to be held about every 10 years. That time frame, it was thought, was sufficient to accommodate the stately progress of scientific research, yet frequent enough to enable researchers in various specialties to come together in a collegial environment to share research results in a timely fashion.

After the summer of 1967, the political winds shifted, and psychedelic substances soon became demonized, feared, and banned. The federal government did not want to sponsor any similar symposia. In fact, its sponsorship of the original symposium, as valuable as it was for the dissemination of research findings, became an embarrassment, and, as a result, no follow-up symposia were held. The symposium proceedings were available for a time from the GPO (US Public Health Service Publication #1645) but eventually went out of print, closing that particular chapter in the history of psycho-ethnopharmacology.

In the 50 years that have passed since the first symposium, numerous federal administrations have come and gone. Our recent past and current administrations, along with most of their affiliated institutions, remain as far from developing a viable, realistic drug policy today as they were then. A new generation of researchers, many inspired by the giants at the first conference, has continued to investigate the outer limits of psycho-ethnopharmacology. Some outstanding discoveries have been made, and the work continues. At the same time, there has been a change in public and medical perception of psychedelics. There is now a renaissance in research around the world, and the therapeutic potential of some of these agents is being reinvestigated. While psychedelic substances have become less stigmatized than in the past, they remain controversial. Much work in this field remains unfinished, and the most significant discoveries may still lie in the future.

How ESPD Changed my Life — Summer 1968

When the first ESPD symposium was held in 1967, I was 16 years old, a bored teenager living in a small town in western Colorado. More than anything, I longed to escape my dreary life and travel to San Francisco, the Mecca for the counterculture and the epicenter of the psychedelic revolution. My late brother, Terence, a lifelong friend and mentor, had escaped our soft prison a few years earlier and was a student at Berkeley at the time. We were both just beginning to discover the wondrous world of psychedelics, and we agreed that they were the most fascinating things that we had encountered in our young lives. The fascination we felt continued to guide our interests and even careers for the rest of our lives.

In 1967, while we were fascinated by psychedelics and wanted to immerse ourselves in the counterculture, neither of us had much of a clue about them. Terence was living in Berkeley, and I managed to get away from my small town and visit him during the height of the Summer of Love. Neither of us was aware of the obscure private symposium that had taken place in San Francisco just a few months earlier.

Like most of our like-minded contemporaries, we had no context in which to understand the emergence of these compounds into mass consciousness in the 1960s. Timothy Leary, PhD, had transformed from a mild-mannered Harvard researcher to the Messiah of LSD, and although much of his message resonated with us, we were slow to plunge full tilt into the hippie movement. This was partly because we identified as intellectuals and, to some degree, were put off by the distinctly anti-intellectual trappings of hippie culture. We thought there had to be more to psychedelics than their superficial depictions in the mass media, but we had no idea where to find a more in-depth and balanced perspective.

Sometime in 1968, while we were busy trying to sort all this out, two books surfaced in our world. These works provided deep background context in which psychedelics made sense to us. One of these books was The Teachings of Don Juan: A Yaqui Way of Knowledge (University of California Press, 1968), which was Carlos Castaneda’s first of many books and described his apprenticeship with a Yaqui shaman.³ Although subsequent events have shown that much of Castaneda’s work is highly fictionalized if not completely fabricated, we did not know that at the time.

For me, at least, that book was influential because it provided a cultural context for psychedelics based on traditions older and richer than anything I had encountered in mass media sources. It made clear that there was nothing new about psychedelics. In fact, these sacred plants and fungi had been used in indigenous shamanic practices for hundreds, if not thousands, of years. While Castaneda’s book was not scientific, or even accurate, it gave me insights into shamanism, a set of practical methodologies and beliefs involving the use of these materials for healing and the exploration of consciousness. Terence gave me a copy of the first edition of The Teachings of Don Juan for my 18th birthday in 1968; it was a very special gift. I still have it, and I still cherish it.

The proceedings of the first ESPD symposium were published some months after the symposium under the sponsorship of the Pharmacology Section, Psychopharmacology Research Branch of the NIMH.⁴

A rather worn copy came into my possession in the summer of 1968. I dropped whatever I was reading and devoured the book from cover to cover. This book provided the perfect balance to The Teachings of Don Juan. While that work had made me aware of the cultural contexts related to the indigenous uses of psychedelics, the Ethnopharmacologic Search for Psychoactive Drugs was even more influential, because through it I became aware that this discipline — ethnopharmacology, or more specifically psycho-ethnopharmacology — was a real field of scientific investigation. Moreover, it was my first introduction to people like Schultes, Holmstedt, Shulgin, Wasson, and others, who became iconic figures in my personal pantheon, and in some cases, as with Schultes and Shulgin, mentors and friends.

The realization that real science was being pursued in this field was a revelation to me, partly because it opened the possibility that one day I, too, might be able to achieve a place in this exclusive fellowship. At first, I thought I would be able to prove to my parents that I was serious about psychedelics and not just a confused hippie in search of cheap thrills, but they were not very reassured. However, over the years, they came to recognize the merits of my chosen career.

Two Decades Later

The shabby volume of that first edition resides on my shelf to this day. While I don’t remember exactly how it came into my hands, I remember very well how my second copy came to me in 1986. I had completed my PhD at the University of British Columbia in 1984 under the supervision of Neil Towers, PhD, another lifelong mentor and friend. My thesis was an ethnopharmacological investigation of the ethnobotany, chemistry, and pharmacology of ayahuasca (Banisteriopsis caapi, Malpighiaceae) and another hallucinogen, a relatively more obscure preparation known as oo’koey, derived from Virola (Myristicaceae) species. Though derived from entirely different botanical sources, both ayahuasca and oo’koey were orally active tryptamine hallucinogens, and my thesis was a comparative study of their active constituents and pharmacology.

After the completion of my thesis in early 1984, I moved to San Diego, California, and began the first of three post-doctoral research projects. About a year after I moved, my thesis publications came out, and one attracted the attention of Juan Saavedra, MD, a researcher at NIMH. When Saavedra requested a reprint of my publication on ayahuasca in the Journal of Ethnopharmacology,⁵ I was surprised. I recognized his name from an early paper he had published with Julius Axelrod on the endogenous synthesis of the psychoactive compound DMT (dimethyltryptamine) in rat and human brains.⁶ (Axelrod later won the Nobel Prize for his work on mechanisms of neurotransmission.)

Figuring it was a long shot, I enclosed a letter with my signed reprint, timidly enquiring if there might be a chance I could come to NIMH and work with him on endogenous tryptamines. A few weeks passed, and one day I received a kind reply. He thanked me for my reprint and mentioned that he had been in the Amazon in 1979 with Schultes and Towers, my mentor, along with a dozen other researchers on the research vessel (RV) Alpha-Helix, operated by the Scripps Institution of Oceanography. He informed me that there was a fellowship program at National Institute of General Medical Sciences called the Pharmacology Research Associate Training (PRAT) that was targeted to young investigators who wanted to expand their scientific training outside their field of specialization. He said it was a perfect fit for me and encouraged me to apply. I did, was accepted into the program, and began my second post-doc in the fall of 1986, in the hallowed environs of the Laboratory of Clinical Pharmacology at NIMH.

I had been in the lab for less than two weeks when Saavedra pointed to an upper shelf in a cabinet in the lab. He said there was a box up there containing some research chemicals that he and Axelrod had used in their research on endogenous tryptamines. He suggested that I go through it and see if there was anything useful, and to send the rest to the hazardous waste disposal center on the National Institutes of Health campus. I didn’t waste any time; I stayed late one afternoon until most of my fellow workers had called it a day, then got up on the bench and retrieved the box. Inside, I found a mint-condition copy of the Ethnopharmacologic Search for Psychoactive Drugs! How many years it had languished on the shelf next to that box of chemicals I had no idea, but it had clearly never been opened.

Here I was, just beginning my post-doctoral studies in the heart of NIMH, the very institution where the original ESPD symposium had originated, and suddenly, the book that had so enthralled me as a curious teenager magically reappeared. How cool was that? I took it as a very good omen. It quietly disappeared into my library, where it sits beside my first copy from 1968. Some of those research chemicals turned out to be interesting as well. Along with a couple of vials of DMT and 5-methoxy-DMT, there was an interesting assortment of other derivatives, such as 5,7-dihydroxy-DMT, 6-methoxy-DMT, and so on. I kept those for many years, but never found the courage to personally bioassay them.

ESPD Returns: 50 Years Later

So, that is the story of my personal history with this book. It has haunted most of my professional career. It opened my eyes to the science of ethnopharmacology, and later, I was fortunate to meet and befriend some of the people who presented at that 1967 symposium. Though its contents are dated now, that book influenced my life and career in profound ways, and I am sure that my career in ethnopharmacology, such as it has been, would never have happened had I not encountered that obscure tome in the summer of 1968.

I have wanted to organize a follow-up symposium for many years. In fact, I first drafted a proposal about it in 1995, hoping to stage it in 1997, the 30th anniversary of the San Francisco symposium. It never happened for various reasons, mostly due to lack of funds, time, and an appropriate venue. In 2017, the 50th anniversary of the ESPD, all of those necessary elements came together almost miraculously.

I hope that the commemorative symposium and the publication of both symposium volumes, 1967 and 2017, will attract the attention of younger investigators working in the field of ethnopharmacology and inspire them to continue this valuable work. There is still more — much more — to be discovered. I hope that the quest represented in the book’s title — The Ethnopharmacologic Search for Psychoactive Drugs — will be carried on by a new generation, who one day will report their discoveries to the world at a future ESPD symposium. I also hope that it will not take another 50 years!

Significant Discoveries of the Last 50 Years

Psycho-ethnopharmacology has not stood still over the last 50 years. Significant discoveries have been made and are still being made. The ESPD50 anniversary conference in June 2017 included presentations on some of the most interesting discoveries of those decades but must necessarily omit many others that are just as worthy. Though it’s not my intention to discuss them in any detail, a few are worth mentioning in brief.

• Ayahuasca Admixtures — The importance of the many ayahuasca admixtures had not received much attention in 1967. Some of Schultes’ students were reporting on the use of the DMT-containing admixtures that give ayahuasca its psychedelic properties, but most of this work was not published until 1968 or later.⁷ Interestingly, the word “Psychotria” occurs only once in the entire 1967 edition. This genus includes Psychotria viridis (Rubiaceae), the most widely used ingredient in ayahuasca admixtures. In the 1980s, Luis Eduardo Luna,PhD, and I also published on the many other species that are occasionally used in these admixtures.^8,9* Many of these remain poorly investigated, both in terms of their chemistry and pharmacology. For a later publication,¹⁰ I screened many of these species using neuroreceptor-binding assays as part of a broad sampling of reported plants with potential anti-dementia and anti-schizophrenic activities. I have contributed a condensed version of that paper in the final section of the 2017 symposium volume.


• Salvia divinorum and Salvinorin A — Although ethnographic reports of the use of this member of the mint (Lamiaceae) family in Mazatec shamanism date back to at least the 1930s,^11,12 it was not discussed during the 1967 symposium. The primary active constituent, the diterpene salvinorin A, was isolated and characterized in the 1990s,¹³ and its potent activity as a highly selective kappa-opioid receptor agonist was described in 2002.¹⁴ This initial discovery has led to a flurry of research on the chemistry and pharmacology of salvinorin A and its analogs. More than 30 papers on salvinorin A have been published since (for a review, see Cunningham et al., 2011¹⁵). Ethnopharmacologist Michael Heinrich, PhD, and his student, Ivan Casselman, contribute a retrospective on this interesting plant in the 2017 volume.¹


• Kava (Piper methysticum) — The term “kava” refers to both the plant in the pepper (Piperaceae) family and the mildly psychoactive beverage prepared from its roots. Kava was reported on during the first ESPD symposium in 1967 (see Session II, ESPD 1967), but much additional work has been done on this plant in subsequent decades. It is now widely available as a dietary supplement, and its anxiolytic, muscle-relaxant, and sedative properties have made it a popular alternative to pharmaceuticals such as benzodiazepines (for a review, see LaPorte et al., 2011¹⁶).


• Kratom (Mitragyna speciosa) — The leaf of this Southeast Asian tree in the madder (Rubiaceae) family is the source of mitragynine and related alkaloids that are mu-opioid receptor agonists. The plant can cause mild addiction like any source of opioids, but in traditional contexts it is often used as an alternative to opium, and as a way to gradually end dependence on opium and heroin. The kratom alkaloids do not seem to cause respiratory depression, unlike heroin and other opioids, and hence show promise as a less toxic, and less addictive, analgesic. Kratom was not illegal in the United States when I first wrote this chapter in 2017, but has been identified as a “drug of concern” by the US Drug Enforcement Administration, and may be scheduled under the Controlled Substances Act in the near future. At the same time, some investigators, such as Christopher McCurdy, PhD, have urged that it not be prohibited because it may enable many opioid addicts to overcome their habits.^17,18 McCurdy has reported on his research and the current “state of the art” with respect to kratom in the second section of the 2017 symposium volume.¹


• Iboga (Tabernanthe iboga) and Ibogaine — Iboga, sometimes spelled eboga, is a West African plant in the Apocynaceae family, used in traditional initiation rites in the spiritual discipline of Bwiti in Gabon. In those rites, young men and women, coming of age as adults, undergo an initiation in which they consume large — sometimes nearly lethal — amounts of iboga root. They experience a deep trance, sometimes lasting up to 36 hours, during which they often claim to experience visits from their ancestors and are initiated and given ancestral wisdom. Ibogaine, the major alkaloid, has received recognition and notoriety, because it is effective for the treatment of opioid and other addictions.¹⁹ Although a Schedule I controlled substance in the United States, it is unregulated in many countries and is used in treatment centers in various parts of the world, especially Mexico.²⁰ Kenneth Alper, MD, a leading authority on the chemistry and pharmacology of ibogaine, contributes “The Iboga Project: Urban Ethnomedicine For Opioid Use Disorder” in the second section of the 2017 symposium volume.¹


• Kougoed (Sceletium tortuosum) — Kougoed, also called channa or kanna, is a South African succulent in the Aizoaceae family whose roots contain a spectrum of alkaloids with central nervous system activities. Some, such as mesembrenone, mesembrine, and mesembrenol, are potent 5HT-reuptake inhibitors and phosphodiesterase 4 inhibitors. These are only three of more than 30 alkaloids that have been isolated from the plant; the pharmacological properties of most have not been thoroughly characterized.²¹ In section two of the 2017 symposium volume, Nigel Gericke, MD, reports on his research with S. tortuosum that has led to the commercial development of Zembrin (HG&H Pharmaceuticals; Johannesburg, South Africa), a natural herbal anxiolytic and antidepressant sold as a dietary supplement.¹


• Jurema (Mimosa hostilis syn. Mimosa tenuiflora) and yuremamine — This Brazilian tree in the legume (Fabaceae) family has long been known as the source of Vinho de Jurema, a psychoactive beverage that contains DMT as its main active constituent. However, it has been an ethnopharmacological enigma because DMT is not orally active unless potentiated by a monoamine oxidase inhibitor (MAOI). Yet, no plants with MAOI activity have been reported to be added to the mixture in traditional shamanism. Recently, a novel compound, yuremamine, was isolated from the roots of M. hostilis at about the same concentration as DMT.²² This compound has an interesting structure, in that the structure of DMT is “caged” within the larger molecule, and it may be a prodrug that is converted to DMT in vivo. The initially proposed structure has been challenged, and total synthesis has so far been elusive.²³ It may also be an MAOI itself, and thus could potentiate the DMT. So far, there have been no human bioassays of this compound, so its pharmacological properties in a pure form are unknown.


• Acacia spp. and tryptamines — The large genus Acacia (Fabaceae) has proven to be an unusually rich source of DMT and other psychoactive tryptamines. At the time of the first ESPD conference in 1967, the tryptaminic Acacia species were unknown to science. The earliest reference in PubMed is Wahba and Elkheir (1975).²⁴ Since then, tryptamines have been detected in more than 60 species of Acacia, as documented in the review paper “Australian Psychoactive Acacia Species and their Alkaloids” by Snu Voogelbreinder in section two of the 2017 symposium volume.¹ Many more Acacia species contain unidentified alkaloids, and phenylethylamines, ß-carbolines, tetrahydroisoquinolines, pyridines, and other structural classes have been reported. Interestingly, much of what science knows about the chemistry of psychoactive Acacia species is due to investigations by amateur scientists who have conducted research outside conventional academic channels, and, as a result, much of it does not appear in the peer-reviewed literature.


• Frog and Toad Medicines — Although obviously neither botanical nor fungal, psychoactive and psychedelic amphibians — frogs and toads — have attracted attention recently as potentially therapeutic. Among these are the so-called sapo medicine, more properly termed kambô, from Phyllomedusa bicolor (the giant leaf frog), a frog containing a variety of neuroactive peptides in its skin secretions. This species is used by the Matsés (Mayoruna) tribe as hunting magic, and taking “sapo” is becoming a popular pastime among tourists in Peru. So far, the peptides identified include phyllocaerulein (hypotensive), phyllomedusin (tachykinin, potent vasodilator, and secretagogue), phyllokinin (a potent arterial smooth muscle dilator), and several delta-opioid-selective peptides, the deltorphins, as well as mu-opioid-active peptides, the dermorphins. Many of these compounds may have therapeutic potential, and the neuroactive peptides are only a part of this rich peptide cocktail. For reviews and more information see Erspamer et al.,²⁵ Daly et al.,²⁶ and den Brave et al.²⁷
  In addition to the Phyllomedusa peptides, the poison of Bufo species contains psychedelic tryptamine derivatives, either bufotenine or 5-methoxy-DMT, and its use has gained popularity in various neo-shamanic practices. Although the subjective effects of Bufo poison were first reported by Weil and Davis (1994),²⁸ there is little evidence that these species were ever utilized as psychedelic medicines in any ethnomedical or shamanic tradition. A comprehensive review of the use of Bufo species as sources for psychedelics, and a discussion of some of the controversies surrounding this practice, can be found in Lyttle et al. (1996).²⁹


• Old Yet New: Harmine and Related ß-carbolines — Harmine is the major ß-carboline and MAOI in the ayahuasca vine. Harmine is an “old” alkaloid, meaning that it has been known for many years, having first been identified in the seeds of Syrian rue (Peganum harmala, Nitrariaceae) by chemist J. Fritsch in 1847, more than ten years before ayahuasca came to the attention of science as a result of explorer Richard Spruce’s discovery in 1858. However, recent investigations have shown that even old alkaloids can still harbor secrets. New research has shown that harmine and some of its derivatives can display a diverse array of biological activities. It has been shown to have antimicrobial, antidiabetic, antidepressant, antitumor, neuroprotective, and other effects. It interacts with a number of neuroreceptors, including 5-HT_2A, 5-HT_2C, imidazoline, and dopamine transporter (DAT) receptors. Significantly, it recently has been shown to be a potent inhibitor of DYRK1A, a kinase involved in a variety of intracellular signaling functions related to cell proliferation and neurogenesis, and has been shown to potently stimulate proliferation of neural cell progenitors, an effect linked to its inhibition of DYRK1A.³⁰ For recent reviews on the pharmacology of harmine and other ß-carbolines, see Cao et al.,³¹ Patel et al.,³² and the paper by Dale Millard (2017)¹ in section one of the 2017 symposium volume.

Conclusion

This article comprises a brief summary of some of the most significant discoveries in psycho-ethnopharmacology in the five decades since the first ESPD symposium in 1967. These findings are only a small sampling of the discoveries that have been made in the last 50 years. The 2017 ESPD50 Symposium — and the publication of the proceedings as a two-volume set that includes a reprinting of the 1967 symposium proceedings — demonstrates that the field of psycho-ethnopharmacology is far from a dead or dying discipline. It is potentially more vibrant than ever. There are still exciting discoveries to be made in years to come. In today’s world, no science can thrive without financial support and academic legitimacy. It is my hope that the publication of this symposium volume will bring a measure of both to this field, and will inspire and excite the next generation of psycho-ethnopharmacologists.

Acknowledgements

The author expresses his profound thanks to those who have made contributions to the 50th anniversary ESPD symposium volume, and the website and e-book that go with it, as well as to the many individuals who saw and shared his vision, and stepped up in so many ways to help make it happen.

* This paper was originally published in Spanish in the journal America Indigena in 1986.⁸ An English translation was published as a chapter in an anthology, Ethnobotany: Evolution of a Discipline.⁹

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