OPEN Foundation

Chemistry

In Memoriam Alexander ‘Sasha’ Shulgin

With great sadness, the OPEN foundation would like to acknowledge the death of maverick chemist Alexander “Sasha” Shulgin, who passed away on June 2nd. Dubbed “the godfather of Ecstasy,” Shulgin was credited with introducing MDMA to psychologists in the late 70’s, years before the drug hit the global dance scene.

However MDMA was only one of hundreds of chemicals Shulgin synthesized during his lengthy career. After earning his biochemistry degree from UC Berkeley in 1954, he worked briefly as research director at BioRad Laboratories before becoming a senior research chemist at Dow Chemical Company, where he synthesized the first biodegradable insecticide, Zectran.

Because Shulgin made Dow a sizeable profit, he was granted the freedom to create and patent new drugs. He chose psychedelics. In the late 1950s, Shulgin experimented with mescaline, which he wrote revealed “that our entire universe is contained in the mind and spirit.” But his interest in pharmacology was sparked years earlier. While in the Navy as a teenager, he got a shot of morphine for an injury, making him wonder how drugs altered consciousness. This passion for understanding the human mind and how to unlock its potential—chemically, of course—would mark his career.

In 1966, Shulgin left Dow Chemical to freelance as a consultant and for the following decades worked from his backyard lab in Berkeley, California. In 1976, he heard about MDMA, which was first synthesized at Merck in 1912 as an unimportant precursor in a new synthesis for haemostatic substances and subsequently shelved. He went on to synthesize it, and discovered it was a powerful empathogen, “with emotional and sensual overtones.” He then introduced it to a therapist friend and word spread quickly both inside and outside the therapeutic community. Without MDMA, the dance music scene of the last 30 years would have looked entirely different.

Shulgin was a fixture in the psychedelic subculture that believed in better living through chemistry. He contributed a rational, scientific perspective to the field, coupled with enthusiasm for thorough self-experimentation.

When interviewed about the abuse potential of MDMA, which became a scheduled drug in 1985, Shulgin was quoted as saying it was “as real as the abuse potential of anything that gives pleasure and satisfaction. This applies to MDMA as much as it does to skydiving, mountain climbing and skiing.”

Shulgin died of several health complications after years of poor health, and had recently been diagnosed with terminal liver cancer. He was 88. His wife, Ann Shulgin, with whom he shared thousands of psychedelic experiences, survives him.

Psilocybin – Summary of knowledge and new perspectives

Abstract

Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, is nowadays given a lot of attention in the scientific community as a research tool for modeling psychosis as well as due to its potential therapeutic effects. However, it is also a very popular and frequently abused natural hallucinogen. This review summarizes all the past and recent knowledge on psilocybin. It briefly deals with its history, discusses the pharmacokinetics and pharmacodynamics, and compares its action in humans and animals. It attempts to describe the mechanism of psychedelic effects and objectify its action using modern imaging and psychometric methods. Finally, it describes its therapeutic and abuse potential.

Tylš, F., Páleníček, T., & Horáček, J. (2014). Psilocybin – Summary of knowledge and new perspectives. European Neuropsychopharmacology, 24, 342-365. http://dx.doi.org/10.1016/j.euroneuro.2013.12.006

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Ibogaine: a review

Publisher Summary

The chapter discusses ibogaine, which is a naturally occurring plant alkaloid with a history of use as a medicinal and ceremonial agent in West Central Africa and has been alleged to be effective in the treatment of drug abuse. The National Institute on Drug Abuse (NIDA) has given significant support to animal research, and the U.S. Food and Drug Administration (FDA) has approved Phase I studies in humans. The chapter discusses the first International Conference on Ibogaine. A major focus of the Conference was the possible mechanism(s) of action of ibogaine. Another important focus of the Conference was to discuss human experience with ibogaine and preclinical and clinical evidence of efficacy and safety. The Conference also featured presentations related to the sociological and anthropological aspects of the sacramental context of the use of iboga in Africa and the distinctive ibogaine subculture of the U.S and Europe. Ibogaine is the most abundant alkaloid in the root bark of the Apocynaceous shrub Tabernanthe iboga, which grows in West Central Africa. The chapter presents a timeline that outlines the historical events relating to the development of ibogaine as a treatment for drug dependence. Ibogaine and serotonin both contain an indole ring in their structure, and ibogaine has been shown to bind to the serotonin transporter and to increase serotonin levels in the nucleus accumbens (NAc). Stereotypy is a methodologic issue that might explain some of the disparate results regarding ibogaine’s interaction with the locomotor response to cocaine.

Alper, K. R. (2001). Ibogaine: a review. The alkaloids: Chemistry and Biology, 56, 1-38. http://dx.doi.org/10.1016/S0099-9598(01)56005-8
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Salvia divinorum: A Psychopharmacological Riddle and a Mind-Body Prospect

Abstract

The multidisciplinary research on Salvia divinorum and its chemical principles is analyzed concerning whether the ethnobotany, phytochemistry, mental effects, and neuropharmacology of this sacred psychoactive plant and main principle clarify its experienced effects and divinatory uses. The scientific pursuit spans from the traditional practices, continues with the botanical identification, isolation of active molecules, characterization of mental and neural effects, possible therapeutic applications, and impinges upon the mind-body problem. The departure point is ethnopharmacology and therefore the traditional beliefs, ritual uses, and mental effects of this Mazatec sacred mint recorded during a 1973-1983 field research project are described. A water potion of crushed leaves produced short-lasting light-headedness, dysphoria, tactile and proprioceptive sensations, a sense of depersonalization, amplified sound perception, and an increase visual and auditory imagery, but not actual hallucinations. Similar effects were described using questionnaires and are attributable to salvinorin A, but cannot be explained solely by its specific and potent brain kappa-opioid receptor agonist activity. Some requirements for a feasible classification and mechanism of action of consciousness-altering products are proposed and include the activation of neural networks comprising several neurochemical systems. Top-down analyses should be undertaken in order to characterize such neural networks and eventually allowing to explore the differential ethnic effects. As is the case for other consciousness-altering preparations, a careful and encompassing research on this plant and principle can be consequential to endeavors ranging from the mind-body problem, a better understanding of shamanic ecstasy, to the potential generation of analgesic, antidepressant, and drug-abuse attenuating products.

Diaz, J-L (2013) Salvia divinorum: A Psychopharmacological Riddle and a Mind-Body Prospect. Current Drug Abuse Reviews, 6(1), 43-53.
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Analytical techniques for the determination of tryptamines and β-carbolines in plant matrices and in psychoactive beverages consumed during religious ceremonies and neo-shamanic urban practices

Abstract

The consumption of ayahuasca, a hallucinogenic beverage used by indigenous communities in the Amazon, is increasing worldwide due to the expansion of syncretic religions founded in the north of Brazil in the first half of the twentieth century, such as Santo Daime and União do Vegetal. Another example is the jurema wine, a drink that originated from indigenous cultures of the northeast of Brazil. It is currently used for several religious practices throughout Brazil involving urban neo-shamanic rituals and syncretic Brazilian religions, such as Catimbó and Umbanda. Both plant products contain N,N-dimethyltryptamine which requires co-administration of naturally occurring monoamine oxidase inhibitors, for example β-carboline derivatives, in order to induce its psychoactive effects in humans. This review explores the cultural use of tryptamines and β-carbolines and focuses on the analytical techniques that have been recently applied to the determination of these compounds in ayahuasca, its analogues, and the plants used during the preparation of these beverages.

Gaujac, A., Navickiene, S., Collins, M. I., Brandt, S. D., & Andrade, J. B. (2012). Analytical techniques for the determination of tryptamines and β‐carbolines in plant matrices and in psychoactive beverages consumed during religious ceremonies and neo‐shamanic urban practices. Drug testing and analysis, 4(7-8), 636-648. https://dx.doi.org/10.1002/dta.1343
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Metabolism and disposition of N,N-dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca

Abstract

Ayahuasca is an Amazonian psychotropic plant tea obtained from Banisteriopsis caapi, which contains β-carboline alkaloids, chiefly harmine, harmaline and tetrahydroharmine. The tea usually incorporates the leaves of Psychotria viridis or Diplopterys cabrerana, which are rich in N,N-dimethyltryptamine (DMT), a psychedelic 5-HT2A/1A/2C agonist. The β-carbolines reversibly inhibit monoamine-oxidase (MAO), effectively preventing oxidative deamination of the orally labile DMT and allowing its absorption and access to the central nervous system. Despite increased use of the tea worldwide, the metabolism and excretion of DMT and the β-carbolines has not been studied systematically in humans following ingestion of ayahuasca. In the present work, we used an analytical method involving high performance liquid chromatography (HPLC)/electrospray ionization (ESI)/selected reaction monitoring (SRM)/tandem mass spectrometry(MS/MS) to characterize the metabolism and disposition of ayahuasca alkaloids in humans. Twenty-four-hour urine samples were obtained from 10 healthy male volunteers following administration of an oral dose of encapsulated freeze-dried ayahuasca (1.0 mg DMT/kg body weight). Results showed that less than 1% of the administered DMT dose was excreted unchanged. Around 50% was recovered as indole-3-acetic acid but also as DMT-N-oxide (10%) and other MAO-independent compounds. Recovery of DMT plus metabolites reached 68%. Harmol, harmalol, and tetrahydroharmol conjugates were abundant in urine. However, recoveries of each harmala alkaloid plus its O-demethylated metabolite varied greatly between 9 and 65%. The present results show the existence in humans of alternative metabolic routes for DMT other than biotransformation by MAO. Also that O-demethylation plus conjugation is an important but probably not the only metabolic route for the harmala alkaloids in humans.

Riba, J., McIlhenny, E. H., Valle, M., Bouso, J. C., & Barker, S. A. (2012). Metabolism and disposition of N, N‐dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca. Drug testing and analysis, 4(7-8), 610-616. 10.1002/dta.1344
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A critical review of reports of endogenous psychedelic N, N-dimethyltryptamines in humans: 1955-2010

Abstract

Three indole alkaloids that possess differing degrees of psychotropic/psychedelic activity have been reported as endogenous substances in humans; N,N-dimethyltryptamine (DMT), 5-hydroxy-DMT (bufotenine, HDMT), and 5-methoxy-DMT (MDMT). We have undertaken a critical review of 69 published studies reporting the detection or detection and quantitation of these compounds in human body fluids. In reviewing this literature, we address the methods applied and the criteria used in the determination of the presence of DMT, MDMT, and HDMT. The review provides a historical perspective of the research conducted from 1955 to 2010, summarizing the findings for the individual compounds in blood, urine, and/or cerebrospinal fluid. A critique of the data is offered that addresses the strengths and weaknesses of the methods and approaches to date. The review also discusses the shortcomings of the existing data in light of more recent findings and how these may be overcome. Suggestions for the future directions of endogenous psychedelics research are offered.

Barker, S. A., McIlhenny, E. H., Strassman, R. (2013). A critical review of reports of endogenous psychedelic N, N-dimethyltryptamines in humans: 1955-2010. Drug Testing and Analysis, 4(7-8), 617-35. http://dx.doi.org/10.1002/dta.422
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Phytochemical analyses of Banisteriopsis caapi and Psychotria viridis

A total of 32 Banisteriopsis caapi samples and 36 samples of Psychotria viridis were carefully collected from different plants on the same day from 22 sites throughout Brazil for phytochemical analyses. A broad range in alkaloid distribution was observed in both sample sets. All B. caapi samples had detectable amounts of harmine, harmaline and tetrahydroharmine (THH), while some samples of P. viridis had little or no detectable levels of N,N-dimethyltryptamine (DMT). Leaves of P. viridis were also collected from one plant and analyzed for DMT throughout a 24-hour cycle.

Callaway, J. C., Brito, G. S., & Neves, E. S. (2005). Phytochemical analyses of Banisteriopsis caapi and Psychotria viridis. Journal of psychoactive drugs, 37(2), 145-150. 10.1080/02791072.2005.10399795
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Various alkaloid profiles in decoctions of Banisteriopsis caapi

Twenty nine decoctions of Banisteriopsis caapi from four different sources and one specimen of B. caapi paste were analyzed for N,N-dimethyltryptamine (DMT), tetrahydroharmine (THH), harmaline and harmine. Other plants were also used in the preparation of these products, typically Psychotria viridis, which provides DMT. There were considerable variations in alkaloid profiles, both within and between sample sources. DMT was not detected in all samples. Additional THH may be formed from both harmine and harmaline during the preparation of these products. The alkaloid composition of one decoction sample did not change significantly after standing at room temperature for 80 days, but the initial acidic pH was neutralized by natural fermentation after 50 days.

Callaway, J. C. (2005). Various alkaloid profiles in decoctions of Banisteriopsis caapi. Journal of Psychoactive Drugs, 37(2), 151-155. 10.1080/02791072.2005.10399796
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Snuff synergy: preparation, use and pharmacology of yopo and Banisteriopsis caapi among the Piaroa of southern Venezuela

Current understanding of the preparation and use of yopo, a hallucinogenic snuff made from the ground seeds of the Anadenanthera peregrina tree, has departed little from the accounts of scientists and travelers made over a century ago. Schultes and others have made refinements to these early accounts. While several scholars have drawn attention to the fact that little ethnographic work has been conducted to assess the ethnobotanical diversity and cultural framework of the snuff hallucinogen complex, few subsequent studies deal with botanical variations in preparation and use. This article contrasts historical accounts of yopo preparation with ethnographic data I have recently collected among the Piaroa of southern Venezuela to demonstrate one way in which yopo preparation and use deviates from the basic model established by Humboldt, Spruce and Safford. Piaroa shamans include B. caapi cuttings in the preparation of yopo and consume doses of B. caapi prior to snuff inhalation concomitant with the strength of visions desired for particular tasks. I argue that the combined use of yopo and B. caapi by Piaroa shamans is pharmacologically and ethnobotanically significant, and substantiates claims of the use of admixtures in snuff; further ethnographic investigation of the snuff hallucinogen complex is necessary.

Rodd, R. (2002). Snuff synergy: preparation, use and pharmacology of yopo and Banisteriopsis caapi among the Piaroa of southern Venezuela. Journal of psychoactive drugs, 34(3), 273-279. 10.1080/02791072.2002.10399963
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30 April - Q&A with Rick Strassman

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