Essential Guide to the
Psychedelic Renaissance

Essential Guide to the
Psychedelic Renaissance

Antón Gómez-Escolar

FOREWORD

In the 1970's and 80's, most psychedelic substances as well as psychedelic research were banned nationally and internationally, despite millennia of traditional use, decades of western scientific studies, and neuroscience discoveries and promising results in mental health treatments (as you will learn in this book). The western socio-political context then was different from today’s, with both social and scientific knowledge about these powerful substances limited. There was little in the way of accurate harm reduction information to effectively minimize the risks of the widespread recreational use, the clinical use was blocked by the massive “war on drugs” propaganda so as not to counteract the misinformation. Psychedelics were lacking more solid scientific knowledge and, as humans, we tend to fear what we don’t fully know, control or understand, so psychedelics were brought to a difficult impasse. In 1986, to break that impasse with new scientific research and knowledge, right after the 1985 scheduling of MDMA, I founded the scientific research and educational nonprofit MAPS, which develops medical, legal, and cultural contexts for people to benefit from the careful uses of psychedelics.

For more than 30 years, despite all the difficulties, the knowledge about these powerful tools was kept and enlarged both underground and beginning in 2000 in clinical research into therapeutic applications, thanks to the conviction of many brave therapists, activists, scientists and organizations, like MAPS, convinced that psychedelics were “as valuable to the mind as the telescope is to astronomy or the microscope is to biology” (to cite Stanislav Grof) and hold an immense therapeutic potential. With the new millenia, the research started giving us its fruits and all this important scientific wisdom started to sprout finally in modern science here and there in the context of the big mental health epidemic unfolding in the western societies over the last decades, an epidemic that current mental health treatments are struggling unsuccessfully to contain. The enormous potential of psychedelics for neuroscience and therapy attracted the interest of many great scientists and institutions worldwide that joined the field and further accelerated the research and the momentum for accepted medical use.

Nowadays, in the midst of a psychedelic renaissance with the potential to transform mental health treatments and our knowledge of the mind forever, esketamine is already approved for depression, Phase III trials with MDMA for PTSD are generating great results, and psilocybin and other psychedelic compounds are researched for many different mental health indications. We have more and more psychedelic knowledge every day. We also have a great opportunity to make all this new scientific knowledge accessible for everyone, to make people understand how and why psychedelic-assisted psychotherapy works, and why all this scientific research is great news for public health. We can finally bring these treatments to those who need them in a context where society understands what, why and how. This is the aim of this book and the collection.

In this this book and the collection it belongs to, you will learn about the basics of psychedelic drugs, the history of the psychedelic renaissance, the new neuroscience discoveries made through psychedelics, and the very promising uses of the psychedelic-assisted psychotherapies to treat many difficult indications like depression, anxiety, PTSD, addiction. You will also learn about the potential risks and practical harm reduction approaches used to prevent these risks inside and outside the lab. As psychedelic substances are now in the process of demonstrating safety and efficacy, it is because we now know more about how to better manage the variables of set & setting to maximize possibilities of a therapeutic outcome and minimize the risk of any problem when psychedelics are taken in a proper therapeutic context with a proper mindset and preparation.

Knowledge is power. To make this psychedelic revolution become an enduring clinical reality for millions of patients and humanity, we need our societies to be well educated in the topic to avoid mistakes from the past and to understand the potential risks and benefits, avoiding the former and benefiting from the latter, like many other cultures around the world have done for millenia. After decades of propaganda and misinformation, a well informed public opinion through books like this is the safe way forward for science, public health and to prevent prohibitionist approaches to drugs as we still face in many places. Despite the amazing results and safety shown for psychedelics in the clinical studies so far, a lot of understanding, work and legal developments are still needed in most countries and societies to keep researching, optimizing and finally bringing these powerful tools to those who need them now for therapy and those who might benefit from them in the future. We need good public and administrative knowledge for more research and to set the basis for an informed debate on how to better utilize the amazing opportunities brought to us by the psychedelic renaissance.

An enduring legacy of this COVID19 pandemic will probably be an aggravated mental health epidemic requiring better therapeutic tools to cope with it, rising awareness about the importance of safe & effective mental health prevention and treatments and the importance of trusting science. As you will read in these pages, science is showing that psychedelics are a powerful tool for mental health treatment and psychedelic-assisted psychotherapy is needed more than ever. Psychedelic research has the potential to change our approach to mental health forever, if we manage to keep educating society and minimizing risky use. After a very long and strange trip, psychedelics might finally be back to stay.

Rick Doblin, Ph.D.

Founder and CEO of MAPS

(Multidisciplinary Association for Psychedelic Studies).

INTRODUCTION TO THE COLLECTION

This is the first of a series of books that will be published within the Psychonaut Guides collection and one that will allow you to learn many things about psychoactive substances in general and psychedelics in particular, as well as the current status of their promising therapeutic uses for a variety of mental health disorders, so unfortunately widespread in our days.

This collection will provide a closer look at these issues, in a simple and didactic way, seeking to bring the subject within reach of anyone with an interest in learning about it, but without neglecting scientific rigor and objectivity, avoiding delving into moral or philosophical questions, and focusing on science, rational knowledge, pragmatism and public health.

In this first volume, which serves as an introduction to the collection, we will begin by introducing the topic of drugs and some of their generalities, seeking to provide the reader with a basic understanding of their types, mechanisms of action, uses and risks, in order to focus then on the specific topic of psychedelic drugs, their recent history, their mechanisms of action, their growing scientific and clinical interest, its legal status, its risks at different levels and how to reduce them as much as possible.

As you will discover in these pages, we are at a key moment to learn about these issues. Not only are there growing movements clamoring for the failure of the "war on drugs" and calling for a revision of the policies in this regard (mainly aimed at decriminalization and even regulation), but there is an important research current that proposes the therapeutic use of some of these psychoactive substances, particularly cannabis (a compound on which we will not focus), and those with psychedelic properties, since they can become very effective treatments for some of the most difficult illnesses we face in mental health today. These substances can be both pure psychedelics (psilocybin, LSD, mescaline or ayahuasca) and empathogenic-entactogenic (MDMA) or dissociative1 (ketamine).

Disorders such as depression, anxiety, addictions or post-traumatic stress, very widespread fundamentally in modern Western societies and very difficult to treat effectively or efficiently, are being treated experimentally, even achieving complete remissions2 in a safe and effective manner through the use of psychotherapies assisted by psychedelic substances (or semi-psychedelic3) in controlled therapeutic contexts. These results have earned recognition from the most important regulatory agencies in the world, such as the U.S. Food and Drug Administration (FDA) and the European Union’s EMA (European Medicines Agency), designating psychedelic-assisted psychotherapies as of great innovative importance and facilitating their research and accelerating their clinical development.

The return of these substances, which decades ago (and in a very different sociopolitical context) were classified internationally as having "a high potential for abuse and no recognized medical value," classification which led to their illegalization, means that we are now rediscovering these powerful molecules that have been used for millennia by many other cultures outside the Western world. For us, this means a real psychedelic renaissance, the beginning of a revolution in neuroscience and mental health that could change our societies forever.

BASIC CONCEPTS OF NEUROSCIENCE AND NEUROPHARMACOLOGY

Before addressing issues of drugs in general and those with psychedelic properties in particular, it is necessary to be clear about some basic notions of neuroscience1 that will allow us to understand both their most basic mechanisms of action and the elementary terminology necessary to be able to speak about them properly. Although you can find some key definitions in the glossary, and in this collection, there are specific publications in the field of neuroscience and neuropharmacology you can examine2. Let’s start by briefly exploring the terrain.

BRAIN AND CENTRAL NERVOUS SYSTEM

In the human body, our thoughts, emotions, behaviors, etc., originate in the most complex and unknown organ we have: the brain.

This organ is located inside our head and is part of what is known as the nervous system, a system that runs throughout our body and performs numerous functions for our survival, such as regulating and maintaining each vital function, controlling voluntary movements, speech, intelligence, memory, emotions and processing the information received through the senses, being the organ where the mind and consciousness of the individual reside.

The brain is the directing part of this complex nerve network that extends throughout the body and allows it to carry out its important functions. Based on these functions and the anatomical structure, human beings divide our nervous system into: Central nervous system or CNS (which includes the brain and spinal cord) and peripheral nervous system or SNP (consisting of all the peripheral nerves that are outside the CNS but connect to it).

Both the central nervous system (CNS) and the peripheral nervous system (PNS) are made up of many different elements and subunits, but the most famous and important are highly specialized cells known as neurons.

NEURONS, SYNAPSES, NEUROTRANSMITTERS AND NEURORECEPTORS

The neuron is the specialized cell that makes up the tissue of the nervous system. In the human brain there are some 80,000 million neurons interconnected through a huge tangle of physical "wires" that extend from their bodies and link them together to form a network. These wires, called axons (which are long and send messages) and dendrites (which are short and receive messages), allow communication between the cells, through chemical and electrical signals that we will see below.

These electrical impulses that travel through the neuron as if it were a wire, are known as action potentials, and could be compared to telegraph messages in Morse code. They are electrical impulses that can propagate within the neuronal "wiring" of the brain and travel long distances through the nerves of the body at very high speeds.

In any cable network there must be "connectors" that link them to each other and to other devices. In the nervous system, those connectors that link the axon of a sending neuron with the dendrites of a receiving neuron are known as synapses, and they are the points where neurons almost touch. But, as they do not really touch each other most of the times, upon reaching these points, the electricity that traveled through the axons (wires) makes some chemical signals "jump": these are the neurotransmitters. So, although neurons use electricity to send messages within the different parts of their elongated body, when it comes to passing that message to other neurons they do so mostly by "splashing" each other with chemicals, called neurotransmitters, which are released when that message in the form of an electrical impulse reaches the end of the axon and must pass on to the next neuron. Although it seems impossible, this process that can seem so complex occurs in intervals of milliseconds, and each neuron can be connected to 10,000 others.

These chemical signals between neurons (neurotransmitters) are quite varied and can send very different messages to the next neuron. We could say that they act as different "keys" that are released by the sending neuron (presynaptic neuron) to the synapse (the connector), and will only fit in some specific "locks" (called neuronal receptors or neuroreceptors) of the receiving neuron (the postsynaptic neuron). Depending on the type of "doors" the receiving neuron wants to open or close, the sending neuron will release one type of key or another.

The substances used by the body to send "non-nerve" messages over long distances or throughout the body are known as hormones3, while neurotransmitters are substances that also send messages but only between neurons and over very short distances, in those synapses we have discussed, producing effects that can be immediate and very localized, or propagate throughout the entire neural network. Some hormones that are generally used by the body can also be neurotransmitters, and some neurotransmitters behave like hormones. However, the key is that the electricity we generally associate with neurons and the nervous system, in reality only occurs within each neuron, the communication between different neurons being fundamentally chemical and based on neurotransmitters, and these are involved in various processes. For example, some of the most famous neurotransmitters are serotonin, known to many as the "hormone of happiness" (although this is only partially true), or dopamine.

Just as there are multiple neurotransmitters that perform different functions, there are several types of neuroreceptors in the membranes of neurons, which are protein structures that act as locks for these keys, and that are activated or not depending on the specific neurotransmitter (key) that comes close to them. For the same neurotransmitter there can be several subtypes of neuroreceptor, so it can even be said that some of them are "master keys" insofar as, sometimes, they can not only open a single lock, but several of the same type, although they do not always turn equally well in all locks. In neuronal communication, what is ultimately important is not so much the neurotransmitter but what happens at the level of the receptors in the postsynaptic neuron, the locks that are being open, and how they do it.

These neurotransmitters and neuroreceptors can serve many different functions both inside and outside the brain, and, depending on the specific region of the brain or neuronal circuit on which they act, they can even be involved in completely opposite processes; so the generalization that a neurotransmitter only has a specific effect is overly simplistic and not always accurate. To give an idea of their diversity and the multiple processes in which they are involved, these are some neurotransmitters with their neuroreceptors and some of their main brain functions:

There are many other neurotransmitters and neuroreceptors, as well as other types of molecules that can act as neurotransmitters, although they are not released in the same way, such as oxytocin (related to emotional bonding, childbirth and breastfeeding) or endorphins (related to analgesia and acting on opioid receptors).

As we can see, all this is not as simple as saying that serotonin is the hormone of happiness, but rather that it acts as a modulator with various functions depending on which of its 14 different receptors it is activating and in which brain region, or neural network, it is found. Other neurotransmitters with fewer receptors can fulfill functions that are easier to explain, such as glutamate, which activates neurons and increases their electrical excitability, or GABA, which "turns them off" or reduces their electrical excitability. But these effects at the neuronal level do not always translate to the entire brain, and it will also depend on the specific networks that are being activated or deactivated.

Why is it so important to talk about how neurons communicate in this book introduction? Because it is this chemical communication between neurons that allows the brain and the other parts of the nervous system to carry out all their functions. Just as it happens inside a computer, the operation of which does not depend only on the work of one of its parts but on the interaction (communication) between many of them, a neuron in our brain does not "think;" the neuronal network does. It is at this point that we can start talking about how exogenous molecules4, like psychoactive substances, influence these processes.

NEUROPHARMACOLOGY

A drug is a molecule that is considered "bioactive" because, due to its structure and chemical configuration, it can interact with protein macromolecules, generally called receptors (locks), located in the membrane, cytoplasm or nucleus of a cell (such as neurons, for example), giving rise to an action and a noticeable effect. For example, when we take ibuprofen, it reduces pain and inflammation. For this reason, pharmacology is the branch of science that studies how the drug (be it a medicine bought in a pharmacy, a medicinal plant or a beer served at a bar) interacts with the body – its actions, effects and properties.

Neuropharmacology in particular studies how some drugs act specifically on neurons and the nervous system. Drugs with the ability to interact with our neurons and nervous tissues are called "psychoactive substances" or "psychoactive drugs," and sometimes simply "drugs", and they cover a wide range of molecules such as alcohol, anxiolytics, analgesics, tobacco, cocaine, coffee, LSD, MDMA, etc.

Based on this definition we can begin to understand why the concept of neurotransmitter (key) and neuroreceptor (lock) is so important to understand, since psychoactive substances (both legal and illegal) act precisely there, on those locks in our neurons. They affect the interaction between our internal keys and our locks, sometimes acting as if they were the keys themselves and opening those locks (agonistic effect), like a pick or false key opens a lock in the absence of the original key; and other times blocking them, as if they were broken keys which fit but do not turn, and not letting other keys in (antagonistic effect). Also, sometimes, they simply make the neurons unable to withdraw those keys after releasing them (reuptake inhibitors), or even "release" more keys than expected (transporter reversals). All these possible actions of drugs in the synapse are what give us such a wide range of possible effects, causing neuronal activations or preventing them, in a way that is different from the normal functioning of the system. They are said to have a certain "affinity" (or fit) for one or more neuroreceptors at a time and can bind to them with lesser or even greater affinity (strength) than our own neurotransmitters.

In essence, it could be said that psychoactive substances act as if they were our own neurotransmitters, but instead of being generated within our own body (endogenous), they enter our body from the outside (exogenous), and their way of interacting with neuroreceptors is different from that of our own neurotransmitters. They are like picks or false keys that can open our locks, even if they are not our own keys.

This happens at the neuronal level, but if we see what happens at the brain level, these changes in the locks of our neurons have a global impact that temporarily changes the way the brain works, and may affect the way different brain regions communicate with each other: overactivating some regions, turning off others, causing incoordination in others. This is what produces the changes in consciousness that we notice, for example, when we drink a beer, drink coffee or consume any other substance with psychoactive properties.

Although much remains to be discovered about the neurochemical processes that form the basis of our consciousness, every day we know more about the basic neurochemistry of our brain functioning, the one that lays the biological foundations of our thoughts, feelings and behaviors. Therefore, every day we have a better understanding of how drugs influence them, and how we can use them to advance science and therapies.