The Neuroscience of Psychedelics: The Pharmacology of What Makes Us Human

Park Street Press

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Park Street Press is a division of Inner Traditions International

Copyright © 2022, 2024 by Genís Ona

Originally published in 2022 as Your Brain on Psychedelics by Argonowta Digital SSL, Madrid, Spain

All rights reserved. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher.

Note to the Reader: This book is intended as an informational guide and should not be a substitute for professional medical care or treatment. Neither the author nor the publisher assumes any responsibility for physical, psychological, legal, or social consequences resulting from the ingestion of psychedelic substances or their derivatives.

Cataloging-in-Publication Data for this title is available from the Library of Congress

ISBN 979-8-88850-004-0 (print)

ISBN 979-8-88850-005-7 (ebook)

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Text design and layout by Debbie Glogover

Creative Commons Agreements: Fig. 40 (CC BY 4.0), Fig. 42 (CC BY-SA 3.0), Fig. 43 (CC BY-SA 4.0)

To send correspondence to the author of this book, mail a first-class letter to the author c/o Inner Traditions • Bear & Company, One Park Street, Rochester, VT 05767, and we will forward the communication, or contact the author directly at genisona.com.

To all subversives, reformers, and agitators.

Your nonconformity and heterodoxy is our hope.

This work has a purely informative and general dissemination function under Article 19 of the International Declaration of Human Rights, which recognizes and protects the right to information. However, the information contained in this work is intended exclusively for persons of legal age.

In no case is the content of this work intended to promote, propose, or provoke the possession, trafficking, production, or consumption of psychoactive substances or any other crime, related or not. The lack of criminal significance regarding the mere personal consumption of psychedelic drugs in most Western countries also means that these aspects cannot be found in a work that only contains informative, bibliographical, and scientific information on a subject of medical-scientific interest, which has a regular presence in the mass media, such as research and therapeutic use of psychedelic drugs and other psychoactive substances, whether legal, controlled, or illegalized.

The publisher and authors disclaim any inappropriate, risky, dangerous, or illicit use that the reader of this work may make of the data and knowledge contained herein. The content of this work, whether of a scientific, medical, legal, or risk-related nature, while seeking to be as rigorous and up-to-date as possible, does not represent a guarantee in any field.

Contents

Foreword by José Carlos Bouso, Ph.D.

Preface

1 Brief Introduction to Pharmacology

Etymological Origins

Main Pharmacological Concepts

Nervous System • Neurons, Synapses, and Action Potentials • Pharmacokinetics and Pharmacodynamics • Neurotransmitters • Receptors • Modifying Receptor Function

Why Psychedelic Pharmacology?

Pharmacology and Complexity

References for Further Study

2 Pharmacological Classification of the Main Psychedelic Drugs: Structures and Major Groups

Simple Tryptamines, including Psilocybin and DMT

Ergolamines, including LSD

Phenethylamines, including Mescaline and MDMA

NMDA Receptor Antagonists, including Ketamine

New Tryptamines

Atypical Psychedelics

Tabernanthe iboga • Salvia divinorum • Datura stramonium

References for Further Study

3 Biological Targets of Psychedelic Drugs

Simple Tryptamine Targets

Psilocybin • DMT and Ayahuasca

Ergolamine Targets

LSD • LSA

Phenethylamine Targets

Mescaline • MDMA

Targets of NMDA Receptor Antagonists, including Ketamine

Targets of New Tryptamines

Targets of Atypical Psychedelics

Ibogaine/Noribogaine • Salvinorin-A • Datura stramonium

References for Further Study

4 Characteristic Aspects of Psychedelic Pharmacology

PHARMACOKINETICS

Initial Phases of the Processing of Psychedelics

Release • Absorption • Distribution

Metabolism

Metabolism and Aging • Main Centers and Enzymes Responsible for Metabolism

Relevant Aspects in the Metabolism of Psychedelic Drugs

Psilocybin • DMT/Ayahuasca • LSD • MDMA • Mescaline • Ketamine • Ibogaine/Noribogaine • Salvinorin-A • Tropane Alkaloids

Elimination

PHARMACODYNAMICS

Therapeutic Effects of Psychedelics

Antidepressant, Anti-inflammatory, and Neuroprotective Effects • Therapeutic Effects of Atypical Psychedelics • Increased Neuroplasticity • Neurological Evidence of Psychedelics’ Therapeutic Effects • Hormonal Effects • Psychological Effects

Microdosing Psychedelics as an Emerging Trend

Adverse Effects in the Therapeutic Use of Psychedelics

Toxicity • Studying the Safety of Psychedelics • Health Risks When Using Psychedelic Drugs Therapeutically

Psychoactive Effects of Psychedelics

Data on Psychedelics’ Psychoactive Effects • Tolerance

References for Further Study

5 Harm Reduction in Your Use of Psychedelic Drugs

Take Care of Yourself • Check What You Bought • Don’t Get Creative with Routes of Administration • Keep Hydrated • Don’t Mix • Be Patient

6 A Look into the Future: Promises and Challenges

Marketing of Psychedelic Therapies

The Role of Traditional Knowledge

To Trip or Not to Trip

Appendix I: The Legal Status of Psychedelic Drugs around the World

Appendix II: Glossary

Index

Foreword

José Carlos Bouso, Ph.D.

Unbounded love. Full acceptance. Absolute understanding. Transformation. Connection. Integrity. Astonishment. Ecstasy. These are some of the most common experiences shared by those who return from a psychedelic adventure—which, experienced in moderation, does not seem to leave anyone indifferent. Far from being a contemporary passing fad, after emerging from a few decades of ostracism to which international drug policies had condemned it, the psychedelic experience has been a common practice in the cultural context of humanity, and of radical importance in the cultural construction of the West. The main philosophers of classical Greece participated in the Eleusinian rites, which were celebrated for some two thousand years until the temple of Eleusis, near Athens, was destroyed by Christian fundamentalism, determined from its inception to placate, with force and fierceness if necessary, all spiritual manifestations other than its own. In Eleusis, the ritual involved the drinking of kykeon, a hallucinogen whose precise composition has not yet been identified, although recognized experts compare it to modern LSD. It seems that the Eleusinian rites were practiced throughout the entire Greek cultural environment, outside of Greece, and this seems to be attested to by a small chalice found in the area of the ancient city Empuries, a province of Girona, Spain, which was supposedly used to drink the kykeon. We can go back even further, to prehistoric times, and find the case of Selva Pascuala, a Neolithic shelter located in the mountains of Cuenca, Spain. The cave contains a parietal mural in which, according to experts, some psilocybin fungi are depicted, which the primitive inhabitants of the region would use to carry out their explorations of non-ordinary ontological territories.

But the use of psychedelics is not exclusive to the Western cultural tradition. The greatest known diversity of plant hallucinogens is found in South America; in Central America there are also numerous archaeological records of the use of various hallucinogenic plants and mushrooms. There are similar records from Africa and Asia, although with less plant diversity. The anomaly of prosecuting users of hallucinogens (the war on drugs is really a war against those who use them) has been very limited in space (the many countries that are signatories to the International Drug Control Conventions, but not their untamed Indigenous lands) and in time (from 1971 to the present day). Just a few decades in what is surely tens of thousands of years of use. A mere hiccup in the history of humanity.

And it seems that this situation is reversing. On the one hand, in most countries, including for example Spain, only the active ingredients of hallucinogenic plants are controlled, not the plants themselves. And in countries where the plants are controlled, like the United States, a social movement is emerging that calls for decriminalization, something that has already been adopted, in fact, in some states and that, as happened with marijuana before, is producing a chain reaction spreading to other states. Psilocybin mushrooms are already sold in stores in Canada, and the government has authorized the compassionate use of hallucinogens (for patients who have had other treatments fail). For the rest of the planet, ceremonies with ayahuasca, psilocybin mushrooms, or peyote are in the process of global expansion (with their pros and cons, like everything else). Cheap and homemade cultivation methods are easily accessible to everyone, and the array of noncontrolled substances available in informal trafficking networks (thanks to prohibition, which has sharpened the ingenuity of society, new drugs were created when the old ones started being controlled) is the largest in the entire history of mankind. So on that front, although there are still occasional arrests and persecutions, things have gotten so out of hand that, in reality, there is no turning back. What will happen in this race ahead remains to be seen, for at least in the case of ayahuasca, peyote, and iboga, plant resources are limited and may not be enough to supply all the people interested in them. It is an element worth reflecting upon.

On the other hand, we find that the active ingredients controlled in the most restrictive lists, such as LSD, psilocybin, mescaline, DMT, or MDMA, to give the most notorious examples, are becoming the subject of scientific research. Some of them, such as psilocybin for the treatment of depression, or MDMA for post-traumatic stress disorder (PTSD), are in such advanced stages of development that they are expected to be available for clinical use by 2023/24. We will then find ourselves in the paradox that for the same substance one can grow at home or buy on the deep web at absurdly low prices, one will have to pay a fortune for a psychiatrist to administer it. We are already seeing this in the case of ketamine for the treatment of depression. A vial of ketamine or S-ketamine (the racemic one that is also used in clinics) costs just two euros, and contains several dozen therapeutic doses. Its equivalent as an authorized medication for depression costs about five thousand euros, containing the same active ingredient, with a different pharmaceutical preparation, and a much higher price. For this reason, the majority of ketamine treatment centers, at least in Spain, continue to use run of the mill ketamine, for obvious reasons. A third option is beginning to emerge in the case of easily accessible drugs, such as MDMA, psilocybin, or ketamine itself: centers are allowing patients to bring the substance, purchased by themselves, and taking it at the consultation under medical supervision.

It will be interesting to see how all these tensions are resolved: on the one hand, as has already been said, the globalization of ceremonies with traditional plants; on the other, the medicalization of controlled hallucinogens and, finally, a possible use of the same active ingredients that are authorized but obtained on the illicit market because of their lower price. In a rational world, we would expect these tensions to be resolved rationally, generating as many possibilities as needed, and where the safety of patients or participants in ceremonies takes precedence. However, in the irrational world we live in, irrational possibilities may include groups asking for the criminal prosecution of other groups; corporatism establishing itself as dominant over other groups (whichever group has the authority to decide the fate of other groups); sensationalism in the media attacking certain ways of doing things and recognizing other ways as the only legitimate ones; and politicians incapable of understanding the complexity of these problems, forcefully applying simple solutions to complex issues, thus generating more harm than good. In short, nothing that we do not already know, having seen the management of similar problems in Spain, for example, from the legalization of cannabis for medical use to the management of the COVID-19 pandemic. Whatever the future holds, its impact will of course be fascinating in the social field. It remains to be seen whether the political and administrative realms will be up to the task and how many victims there will be before that happens, if and when it happens.

That is why a book like this is so pertinent now. It does not deal with social issues, but rather brings us up to date on the current scientific knowledge of the functioning of all these substances, for which so many names have been sought, without consensus. In this book about such an arduous discipline as pharmacology, the young psychologist and pharmacologist Genís Ona makes an informative, entertaining, and, as far as the subject allows, understandable approach to the pharmacology, psychopharmacology, and neuropharmacology of hallucinogens. To understand the pharmacology of hallucinogens is to understand the essence of what makes us human: beings capable of experiencing those ineffable sensations with which this foreword began. Hallucinogens allow us to access unusual spaces of reality, thus becoming a source of knowledge, not of psychopathology. This is how they have been used since time immemorial, and this is also the most interesting way of contemporary use. It is still paradoxical that when the therapeutic value of hallucinogens is recognized (once their safety and efficacy as drugs to treat mental health problems have been demonstrated), what is being implicitly recognized is the therapeutic value of hallucinations. And, perhaps, parallel to this, a less pathological view of some human psychological experiences that are currently considered diseases will begin to emerge, despite the lack of evidence on their physiopathogenesis.

In this sense, Genís Ona also wonderfully guides us along the path of pharmacological research and its direction—how, in the years when psychedelics were considered psychopathology-inducing substances, the mechanisms by which they produced aberrant psychological effects were sought in their neuropharmacology (the interest back then being the cause of diseases such as schizophrenia). Today the outlook is quite different and we find studies where hallucinogens have been shown to improve prosocial behavior or counteract the neurobiological mechanisms of anxiety. So we have gone from looking for the bases of human psychopathology to exploring the bases of its healing mechanisms. The curious thing about the matter is that the mechanisms are the same and what varies is the way in which they are viewed. Before, they were viewed as the mechanisms by which our brain developed schizophrenia and today they are viewed as the ones that can cure depression. The scientific investigation of hallucinogens is the best example of how science is not as objective as some claim it to be but is as imbricated in social context as any other human activity. Social context will decide what hallucinogens are useful for, and that is what will guide their pharmacological research, yielding better insight into their neurobiological bases.

But why a book on the pharmacology of hallucinogens? What is so interesting about pharmacology to dedicate a popular science book to it? Beyond what the author already comments in his introduction, that is, that although we do not talk about the mechanism of action of drugs in our everyday lives, medicines are in fact part of that daily life, and it never hurts to know something about what they do to our body (and what our body does with medicines). In the case of hallucinogenic drugs, the interest, in my opinion, is enormous. We are talking about substances with a minimal effect on the body that induce a maximum state of consciousness. Hallucinogenic drugs are that link between the extremely material (our body) and the extremely spiritual (our conscience absolutely exposed). In a way, hallucinogens are a kind of philosophers’ stone that, when in contact with a series of brain receptors, produces an amazing transformation of reality, in which, on the subjective plane, the spiritual is separated from the physical. The subjective experience with hallucinogens is therefore extremely spiritual: in its peak effect, the body disappears and only the spirit remains, at the mercy of transformation, in its most radical essence—a sentient, knowing, and understanding spirit. For Indigenous cultures, hallucinogens are the vehicle to enter a spiritual territory that is as real, if not more so, than reality itself, from which rise myths, cosmogonies, and the knowledge of the origins of disease and its sources for correction, where the shamans carry out their medical acts. Their concepts of health and disease have nothing to do with ours. And, Westerners being so spiritually illiterate, these substances allow us to access understandings about the nature of reality that can later serve us in our daily lives, as much therapeutically as ontologically and transcendentally (one of the uses of psychedelics being recovered is precisely in patients with terminal illnesses, preparing them to face death). If this is so, then knowledge of the pharmacology of hallucinogens consists of trying to understand the mechanisms by which this knowledge itself is produced. It could be said that the pharmacology of hallucinogens is actually a philosophical discipline that is studied through scientific methods commonly used in psychology and biology.

Pharmacology is the science that studies the effects of drugs on the body. In the case of hallucinogenic drugs, there are two subdisciplines of particular interest: psychopharmacology, which is the study of effects on behavior, and neuropharmacology, which is the study of effects on the nervous system. In the first, the study is carried out using tools developed by psychology such as psychometric questionnaires, and in the latter, with tools from neurology (the study of receptors and mechanisms of action). It is a complex science, since relating psychological processes with neurobiological mechanisms is not an easy task. All this aside from the risk of trying to explain phenomena belonging to different levels of analysis, one with the other’s categories. The most current example is that of the famous default mode network construct, so popular in current neuroscience in general, and in that of hallucinogens in particular. I leave it to the reader to get to the corresponding part in this book, to see how easy it is to fall into this type of bias, and how the author solves it so accurately. And similarly, many other examples that only a person with mixed training in psychology and pharmacology, together with great experience in the empirical field, can draw our attention to and clarify.

In this sense, Genís has been able to place each explanation at its corresponding level of analysis, thus avoiding the reductionisms that are so typical of this field. In a context in which biomedicine is dominating research agendas and budgets, even though its clinical application is extremely limited compared to other approaches, based mainly on public health or social and community practices, the author wanted to reflect on its scope and limitations and devote some final chapters to the reduction of risks in the use of hallucinogens and the recognition that should be given to traditional societies, which are ultimately the discoverers of many of these compounds. If in our society we establish mind-brain relationships in accordance with the parallel advances of both neurobiology and psychology, a field of extremely interesting value will be one to connect these disciplines with traditional Indigenous knowledge in relation to hallucinogenic plants and compounds. In his essential book Consilience: The Unity of Knowledge (1998), the recently deceased biologist Edward O. Wilson already pointed in that direction, precisely using ayahuasca and one of its best-known cultural expressions, the art of the Peruvian mestizo painter Pablo Amaringo, as an example.

In short, what we have here is an a priori arduous field, which becomes attractive when we understand that its concepts reveal the keys that will allow us to go deeper and deeper into the knowledge of what is the essence of the human being. Hallucinogens, as writers like Aldous Huxley or chemists like Alexander Shulgin have said, are incomparable tools for learning about mind-brain relationships. And the discipline that deals with this study is pharmacology. The last twenty years have been vertiginous in terms of the development and progress in knowledge of the pharmacology of hallucinogens, but this knowledge is only present in scientific journals; it has not reached the general public. That is why this book is so pertinent at this time. We needed a translator, a compiler who could bring what is in that inaccessible world of scientific literature down to Earth, a feat that can only be achieved satisfactorily if the one doing it can masterfully combine scientific knowledge and humanistic sensibility in such a way that scientific abstraction can be understood in its social context. In the case of Genís Ona, these two types of knowledge coexist, allowing him to move away from literal and reductionist explanations, without avoiding the complexity of the phenomena and making precise interpretations of the data.

Writing a book like this was no easy task, if one did not want to betray the goal of making it for all audiences. My congratulations to the author. I think he can feel satisfied with the result. If an intellectually restless person seeks to know the processes that mediate between matter and spirit, how these processes have been discovered, what philosophical and therapeutic implications they have, and, above all, to update on the level of knowledge that is now available about them and their relationship to hallucinogenic or psychedelic drugs, this is your book. I can be nothing but proud for having been asked to write a foreword by the author, the only independent researcher in Spain who is currently administering hallucinogens in clinical settings to study their pharmacology and therapeutic potential. And someone who, in addition to being a tireless collaborator, is a good friend. Genís’s resumé, by the way, in terms of scientific publications in impactful journals, exceeds the average researcher, and more so in a field as complicated as psychedelic research has been, until relatively recently. This book is therefore another small success in his already brilliant career, of which I am sure we will all feel proud in the future, even more than we feel now. Researchers like him are role models for this coming generation, of which he is a part, to lead the way in psychedelic research.

José Carlos Bouso, Ph.D.,

Scientific Director of ICEERS

José Carlos Bouso is a clinical psychologist with a Ph.D. in pharmacology. He developed his scientific activities while at the Universidad Autónoma de Madrid, the Instituto de Investigación Biomédica IIB-Sant Pau de Barcelona,