Schedule 1 Research Protocol: An Investigation of Psychedelic Plants and Compounds for Activity in Serotonin Receptor Assays for Headache Treatment and Prophylaxis

Winter 1996/97 Vol. 07, No. 1 Learning to Crawl

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With partial support from MAPS, a group of researchers is pursuing the study of plants and substances with reported psychedelic properties for activity in serotonin receptor assays that may indicate therapeutic utility in acute or prophylactic treatment of migraine headache syndromes.

Ethan B. Russo, M.D.
Department of Neurosciences
Western Montana Clinic
Missoula, MT 59807-7609

Plant analgesics

For thousands of years, medicine and plants were synonymous. The first analgesics, willow bark and the opium poppy, yielded pharmaceutical derivatives we now recognize as aspirin and morphine. In the 1930’s, research on Claviceps purpurea, the fungus of rye grain by Sandoz Laboratories, led to the development of the ergot alkaloids, the first truly effective pharmaceuticals for the treatment of migraine headache. This research led as well to an unexpected by-product, Albert Hofmann’s "Problem Child," lysergic acid diethylamide, a psychedelic with profound implications for neurochemical investigation. As a practitioner of allopathic medicine and neurologist, the principal investigator has continued a long-standing personal interest in herbal medicine and ethnobotany, and feels that additional mysteries in the treatment of neurochemical disorders may be solved through a renewal of investigation of "nature’s chemists," the plants.

Embarking on new research

In 1990, recognizing the continued need for new symptomatic and preventive drugs for treating migraine, this research group embarked on a survey of available ethnobotanical information from around the world with reference to headache treatment. Very quickly, it became apparent that the area of greatest plant biodiversity, the Northwest Amazon, was also the site of the most numerous ethnobotanical treatments for headache. Also in that year, publications outlining the neurochemical basis of migraine treatment in serotonin receptor pharmacology suggested the plausibility of employing these laboratory techniques as an in vitro method of screening plant extracts for possible development as new therapeutic medicinals. In 1992, an article was published by the principal investigator in Journal of Ethnopharmacology, outlining these theories, and how they might be applied to 24 plants used for headache treatment by indigenous peoples of the Ecuadorian Amazon. A field study of these plants with collection and subsequent laboratory analysis was proposed. Subsequently, two University of Montana Research Grants, totaling $5000 in awards, were assigned to these investigations. In 1994, Drs. Russo and Medora traveled briefly to the Amazon, but plans to do preliminary plant collection in Peru were not approved by that government.

Plant collection in Peru

In 1995, in association with Glenn Shepard, a doctoral degree candidate in anthropology at the University of California, Berkeley, the principal investigator accomplished this goal in two months of ethnobotanical field study of the Machiguenga people of the village of Yomuibato in the midst of the remote Parque Nacional del Manz, in southeastern Peru’s Madre de Dmos department. During this sojourn, in excess of 400 medicinal plant species were collected for botanical identification. Of these, fully 25% had indications suggesting neuropharmacological activity, including migraine. Of approximately 25 species on a "wish list" for plants employed for headache, all but two were identified in Manz, but in addition, many novel specimens were collected. These were preserved in ethanol, and in some instances, live specimens were exported in accordance with Peruvian and U.S. statutes, and have survived the difficult outward journey to be cultivated in Montana. We believe that there are several species new to science, and preliminary investigation through NAPRALERT searches confirms that very few have undergone any biochemical analysis. Further details of this work are available on the net: "Plants of the Machiguenga," Initial studies to date, undertaken by Drs. Keith Parker and Rustem Medora of the University of Montana Department of Pharmacy, and Dr. Chuck Thompson of the Department of Chemistry, have revealed very encouraging results in demonstrating the activity of several plant extracts on serotonin receptor activity. Approximately ten Machiguenga samples are ibenkikis, Cyperus species infested congenitally with Balansia fungus that have demonstrated the presence, in prior study, of novel ergot alkaloid structures. These hold obvious promise for additional study in migraine treatment and the search for other psychoactive agents. It is of interest that numerous plants used ethnobotanically for headache are psychedelic at higher doses.

Migraine medications

As late as 1915, Sir William Osler, an acknowledged father of modern medicine, touted Cannabis as the most effective treatment available for migraine. The same seems to be true of synthetic medications for migraine. After all, sumatriptan (Imitrex) is merely dimethyltryptamine (DMT) with a methanesulfonamide in the 5-position. Similarly, if the methoxy group on methysergide (Sansert) is changed to an ethyl, one has produced lysergic acid diethylamide (LSD). In fact, methysergide and ergonovine, prescription medications for migraine, are themselves psychedelic at high doses. The Machiguenga tribe employs intraocular administration of fresh Psychotria leaf juice as a treatment for migraine. It is apparently quite effective, and free from bothersome side effects. Another species, Psychotria viridis, is well known as a DMT-donor in the ayahuasca admixture employed by many Amazonian tribes as a preparation for psychedelic divination. As an estimate, the Machiguenga utilize 15-20 Psychotria species for one psychoactive purpose or another. There is good potential for discovery of novel tryptamine analogues with clinical application from these plants. The Machiguenga employ or have employed several plants beyond these with reported psychedelic activity that have not previously been reported, let alone characterized pharmacologically. We have ethanol samples of these, and a few are in cultivation in an "Amazonian Jungle in Exile."

Serotonin receptor assays

In short, the investigators believe there is high potential among existing plant samples and live plants to identify additional good candidates for the serotonin receptor assays. As time and funding allow, we hope to continue and complete the surveys on those agents. However, for the reasons described above, the researchers do not feel that our search should end there. We recently received $1,500 from the American Gloxinia and Gesneriad Society for study of psychoactive and headache plants from that family (which includes African violets). A generous $2500 grant has been received from MAPS, and will be utilized to purchase reagents and necessary laboratory assistance. We have arranged for the subsequent forwarding of marijuana samples from the University of Mississippi, pending receipt of a Schedule 1 Drug Permit (application submitted). Ideally, we would like to study all three species, Cannabis sativa, indica, and ruderalis. It is suspected that THC itself will have generous serotonin receptor activity, in keeping with Cannabis’ long history as a migraine remedy. Perhaps these plants contain other active analogues that are not Schedule 1 substances. Since the discovery of anandamide as the endogenous ligand for the cannabinoid receptor in the human brain, some semi-synthetic efforts in that area may be similarly fruitful in treating migraine and other painful conditions. A permit is similarly sought for the study of Psilocybe mushrooms, to be provided by Paul Stamets of Fungi Perfecti in Washington state. It is likewise sensible to study peyote, should a source of supply be identified, and other mescaline-producing cacti, such as Trichocereus (Echinopsis) pachanoi. Similarly, the investigators propose to obtain small amounts of 5-methoxy- dimethyltryptamine (5-MeO-DMT), dimethyltryptamine (DMT), diethyltryptamine (DET), and dipropyltryptamine (DPT). These compounds will likely be strong ligands in the serotonin receptor assays, and thus may be active against headache at doses sub-threshold for psychedelic effects (say 1 mg. or less), much as the raw leaf juice prepared from the Machiguenga’s Psychotria suggests.

Logical next steps

One obvious issue in this research project is how potentially psychedelic drugs could putatively be safely marketed for patient use. It would be practical to package a commercial product (eye drops or nasal spray) in single or few-dose packaging that would avoid the risk of abuse. Likely, these might necessarily be Schedule 2 drugs, requiring non-refillable, written prescriptions, much as is the case for methadone or dronabinol (Marinol, synthetic THC). They would have the advantage of rapid parenteral absorption, without injection, but obviating the oral route with its slow onset and unreliable absorption rate due to attendant gastroparesis in migraine. However, it bears repeating that methysergide and ergonovine are psychedelic at high doses, but are not subject to these more rigid controls. Although the current study is not designed to include either animal or human clinical studies, should the biochemical assay results support con-tinuing investigation, we would then apply for permission to pursue the logical next steps. Dr. Russo will be the principal investigator, but all the actual research will take place in the research laboratories of the Pharmacy and Chemistry Departments of the University of Montana, Missoula, Montana. In addition to the Machiguenga samples collected in Peru, planned study items include, but may not be limited to:

Marijuana: Arrangements will be made with the University of Mississippi, to obtain small amounts (circa 100 g.) of Cannabis sativa, and additionally as available, Cannabis indica, and Cannabis ruderalis, for analysis, serotonin receptor assays, and the possible discovery of new compounds in the plants with serotonin receptor activity.

  • THC (tetrahydrocannabinol): small amounts (circa 1 g.) for baseline chromatographic and NMR standards.
  • DET (diethyltryptamine): 5 mg. or less, for structure-activity studies, and new compound synthesis.
  • DMT (dimethyltryptamine): 5 mg. or less, for reference standards, structure-activity studies, and new compound synthesis.
  • 5-MeO-DMT (5-methoxy-dimethyltryptamine): 5 mg. or less, for reference standards, and new compound synthesis.
  • DPT (dipropyltryptamine): 5 mg. or less, for structure activity studies, and new compound synthesis.
  • Mescaline (3,4,5-trimethoxy-beta-phenethylamine): 5 g. or less, for reference standards, and new compound synthesis.
  • Peyote: small amount, 500 g., if supply can be procured, for analysis, serotonin receptor assays, and possible discovery of new compounds.
  • Psilocin (4-hydroxy-dimethyltryptamine), Psilocybin (O-phosphoryl-4-hydroxy-dimethyltryptamine): 1 g. or less of each, for reference standards, and new compound synthesis.
  • Psilocybian mushroom species: 1 kg. or less, to be supplied by Paul Stamets, of Fungi Perfecti, for analysis, serotonin receptor activity, and possible discovery of new compounds.

Hopes for human studies

Although the grant money to date will allow preliminary work to commence, hopefully during the 1996-97 academic year, carrying the project to its desired end-point will likely incur costs many orders of magnitude greater. The researchers are dedicated to the ethnobotanical and chemical search for better clinical pharmaceuticals for migraine, depression, and treatment of pain. Listing of drugs as "Schedule 1" presupposes that they have no clinical utility, and has road blocked necessary research until 1990 when the FDA began approving human studies with psychedelics. The lingering controversy over such research has effectively cut off this project from any likelihood of public funding. The difference will need to be raised from interested private sources. Tax-deductible donations from interested parties will be gratefully received by MAPS (please specify that you want 100% of your donation to go to Dr. Russo’s migraine project), or can be sent directly to:

Ethan Russo
M.D., Department of Neurosciences
Western Montana Clinic, 515 West
Front Street
Missoula, MT, 59807-7609