Doors of perception: without psychedelics, there would be no neuroscience

© Manuel Fernandez

Science is gradually rehabilitating psychedelics, with interest in experimental studies of psilocybin and other psychoactive substances resurgent. It’s useful to remember where it all started: in the 1960s, consciousness-expansion experiments were a storehouse of new information for psychotherapists and neuroscientists. In particular, it was thanks to them that the role of serotonin in the functioning of the brain was clarified - and from this discovery all modern psychopharmacology grew.

In the mid-twentieth century, the prevailing hypotheses in psychology and psychiatry were that mood, desires, feelings, memory, behavior, and personality are caused by the environment, childhood experiences, the interrelationship of reward, punishment, repression, and reinforcement of the subconscious mind, and, among others, psychosexual mechanisms. Brain activity was thought to be electrical in nature. Until the 1940s and early 1950s, the view that consciousness is influenced, if not conditioned, by the action of chemicals produced in the brain was entirely alien to the medical environment. Important events that have influenced the change of existing paradigms and gave rise to neurochemistry and neuropharmacology and led to the direct development of psychopharmacology as a scientific discipline, are actually centered around the discovery and study of the psychoactive effects of lysergic acid diethylamide (LSD), N, N-dimethyltryptamine (DMT), psilocybin and other psychedelic substances.

Perhaps the most important discovery in psychedelic research was the role of serotonin in mental processes. Serotonin, whose chemical structure was determined in 1949, has been known since the late 1800s. Here we discover its hemostatic role: when tissues are damaged, it helps prevent bleeding. In the case of injury, serotonin is released from platelets, causing local vasoconstriction and stimulating further platelet aggregation, helping to form a clot and stop bleeding. Serotonin was also discovered in brain tissue in the early 1950s, indicating its potential role in brain function and consciousness. The detection of serotonin in the brain was done independently and simultaneously by a team of scientists in the United States and another team of scientists in Edinburgh, Scotland, led by Sir John H. Geddam. However, in the formation of early theories regarding the participation of serotonin in the processes of consciousness, Geddam’s experiments with LSD carried out on himself were of particular importance.

Sir John H. Geddam, a British pharmacologist, was involved in the initial serotonin research. Geddam took LSD four times in 1953 to learn about its effects on his body. No doubt, partly through these experiments on himself and partly through his laboratory experiments with LSD and serotonin, Geddam was the first to suggest a link between LSD and serotonin, and then to assume that the effects of LSD on serotonin function were responsible for the psychedelic effects of LSD. His handwritten notes on a self-experiment with 86 micrograms of LSD on June 1, 1953 read: 9:48 My hand looks strange, like a monstrous drawing of a hand that wriggles until I focus my eyes on it. She has amazing color contrasts. I see more than a real drawing, which evokes a rather strange feeling – as if it belongs to someone else. Everything in the room is quite unstable.” Methedrine did not eliminate the effect on sensations. “Evidence for the presence of HT (serotonin) in some parts of the brain can be used to support the theory that the mental effects of lysergic acid diethylamide arise from interference with HT (serotonin).” Thus, in the personality of Sir John Geddam, there was a fusion of personal experience of LSD use and scientific understanding, which gave rise to the birth of chemical neuroscience.

“Endogenous DMT plays an important role in states of consciousness such as enthusiastic state, daydreaming, creativity, clinical death.” Independently, D. Woolley and E. Shaw in New York proposed, “...that mental disorders caused by lysergic acid diethylamide should be attributed to the interference of acid with the action of serotonin in the brain.” In addition, they state that “Geddam was also aware of the mental effects of lysergic acid diethylamide and the effects of serotonin in the brain. We assumed that he was thinking the same thing as we were, about the relationship of serotonin to the mental disorders caused by the substance.” Unlike Geddam, there is no evidence of Woolley or Shaw taking LSD.

These pharmacological discoveries indicate that serotonin plays an important role in mental processes, and that suppressing its action causes mental disorder. In other words, the lack of serotonin is the cause of the disorder. If the deficiency of serotonin in the central nervous system is the result of metabolic disorders, and not caused by pharmacological agents, you can expect the manifestation of the same mental disorders. Perhaps this deficiency is responsible for the natural appearance of diseases. Thus, we make the following assumptions: serotonin probably plays a role in maintaining normal mental processes; lack of serotonin caused by metabolism may contribute to the appearance of certain mental disorders; serotonin, or its long-acting derivative, may alleviate mental disorders like schizophrenia.

In these early reports, one can see the source of the current research and development of modern psychotherapeutic drugs that spawned a billion-dollar pharmaceutical industry aimed at changing the action of serotonin and other neurotransmitters in the brain to treat mental illness.

DMT has also greatly influenced the evolution of our understanding of normal and extraordinary states of consciousness. In 1961, Nobel laureate Julius Axelrod made a remarkable discovery: mammalian tissue (the lung of a rabbit) has the ability to synthesize DMT.

This discovery was extensively investigated in the early 1970s when it became known that human brain tissue undergoing biopsy could perform the same biotransformation. The discovery that human brain tissue can produce, at least in the laboratory, small amounts of DMT has led to heated debate about the possible role of DMT in human consciousness. However, the analytical technologies of the time were not as sensitive or reliable as they are today. While some researchers have been able to confirm the presence of DMT in human tissues and fluids, others have failed. Some scientists at the time believed that the result of laboratory observations by Axelrod and other researchers was more an artifact than an objective phenomenon. The issue remained unresolved for almost 30 years. Then, in 1999, Michael Thompson and his colleagues at the Mayo Medical Institute in Rochester, Minnesota, using molecular biology techniques — cloning and sequencing — discovered a human gene that encodes an enzyme that synthesizes DMT from tryptamine. Thompson’s discovery revived numerous discussions and fully strengthened the hypothesis that endogenous DMT plays an important role in states of consciousness such as enthusiastic state, daydreaming, creativity, clinical death, and others. The view that the presence of DMT in mammalian tissues is just an artifact not peculiar to the object and distorts the results of the study was untenable.

Since Geddam, research on psychedelics, serotonin and other neurotransmitters and their receptors has continued at an accelerated pace. Based on the early theories of Geddam, Wooley, and Shaw about the role of serotonin in the pharmacology of LSD, in the 1980s Richard Glennon and colleagues at the Virginia Commonwealth University Graduate School of Pharmacy were the first to determine that the serotonin receptor 2- (now called the type 5-HT2A receptor) is the primary target binding psychedelic agents such as lysergamide, phenylalkylamine, and indolalkylamine. Over the next two decades, additional binding sites were discovered; 40 or more additional receptor sites of psychedelic drugs are now distinguished. Although 5-HT2A is still considered a common receptor for psychedelic drugs, more and more researchers are concluding that the activity in this receptor alone is insufficient to explain all the effects of psychedelics.

Apparently, the simultaneous action of psychedelic drugs on many or even all 40+ currently identified receptor sites, while each psychedelic agent has a unique receptor binding and activation profile (pharmacological “fingerprint”), forms a lot of subjective sensations caused by these substances. Thus, although the term “psychedelic” is often used as a simplistic term, psychedelic substances, although they cause similar subjective effects in humans, do not produce the same subjective effects that people taking these drugs readily report. The effect of LSD is quite different from that of mescaline, which in turn differs from that of DMT, which differs from TMA-2, which differs from psilocybin, which differs from that of 2C-B, etc. Although in vitro and animal behavioral data are commonly used to study these materials, these approaches are limited in that they tend to blur qualitative, empirical differences between psychedelic drugs — differences that humans can easily identify. Test-tube data and animal data can complement, but not replace, human experience, which is undoubtedly a prerequisite for testing psychedelic effects.

The problem of defining uniform criteria for determining psychedelic substances and the experiences they cause is certainly not new. As Alexander Shulgin said: “If there is confusion in the choice of the term to describe the class of drugs that we will call [psychedelic drugs], then when we agree on the description of their action, we will come to a complete confusion.” One approach proposed in the 1970s was to define psychedelics as agents that mimic the effects of LSD.

Although this definition is self-contained, it has placed psychedelic experience at the heart of the discussion. Lester Green Spoon and James Beckalar proposed: “A drug will be considered psychedelic or not, depending on how and in what way it resembles LSD; the similarity must be judged by the cultural role of the drug, as well as the range of its psychopharmacological effects. From this point of view, the group of psychedelic drugs has a well-defined center and a blurred periphery.

Research using psychedelics provides a deeper understanding of brain function and continues to have an impact on psychopharmacology. Linking the molecular action of the drug to animal behavior and human experiences remains a tempting but not fully realized goal. Much of the progress that has been made in this field has been made possible by the work of Alexander Shulgin, who developed, synthesized and characterized more than 200 new psychedelic substances in his private laboratory. Shulgin compounds have been used by many other scientists around the world to study receptor binding and drug activation in the laboratory, for computer modeling of substances and mapping receptor shapes, to study the electrical activity of neurons, to study animal behavior, etc. Shulgin’s work has also contributed significantly to the diversity of human psychedelic experience.

From the review of the literature above and from other sources, it is clear that much of the current research on neurotransmitters and drugs that affect their function in the brain can be traced back to the experiments and work of scientists studying the mechanisms of action of LSD, DMT and other psychedelic compounds.

In light of these discoveries in neurochemistry, the assumptions of psychology and psychiatry regarding the origin and nature of consciousness and mental illness have had to be revised. It has become necessary for psychology and psychiatry to incorporate the observations of neuroscience into models of mental functioning. Neurochemistry and neuropharmacology began to play a dominant role in the study of consciousness and in the treatment of mental illness by the late 1950s and 1960s. For example, for psychotherapeutic practices, it became mandatory to use psychoactive drugs, which were obtained on the basis of experimental discoveries of neuropharmacology, as the main approach for psychological treatment. Thus, psychopharmacology emerged as a medical and scientific discipline. While there is still much that can be improved, the effectiveness of these drugs has undoubtedly saved countless lives.

Although clinical research on psychedelics in humans was temporarily suspended in the late 1960s and 1970s, research into their underlying chemistry, pharmacology, and neuroscience continued. In scientific circles, research with chemical synthesis and pharmacological research of psychedelic drugs was concentrated in the laboratories of the aforementioned Richard Glennon and David Nichols at Purdue University College of Pharmacy in West Lafayette, Indiana, George Aghajanian at the Yale University School of Medicine in New Haven, Connecticut, which greatly contributed to our understanding of the effects of psychedelics on the neural signaling system and brain system. Other scientists, whose names we will not mention because of their abundance, used different animal behavioral models to study these substances. Current academic research focused on the study of psychedelics takes place in various pharmaceutical and medical institutes and in the departments of medical chemistry, neurology, pharmacology, psychology and psychiatry. If the interested student is diligently studying the scientific literature (PubMed is perhaps the most useful tool for this), potential research opportunities can be identified in educational institutions around the world.

For a person who is seriously interested in such research, especially if it involves psychedelic drugs, a PhD or medical doctorate is essential for academic or clinical research. Several years of postdoctoral training may eventually lead to the role of principal investigator of basic scientific work or head of clinical research dealing with human research. In any case, after obtaining a bachelor’s degree and entering graduate school, the number of opportunities in this field will increase, whether it is the role of a team member in conducting research with psychedelic drugs at a university, a pharmaceutical company, the National Institutes of Health or a private research foundation.

As described above, psychedelic drugs have been used over the past few decades to answer mechanistic questions about receptors, neural processes, and animal behavior. Research using psychedelics provides a deeper understanding of brain functioning and continues to influence psychopharmacology and the development of drugs for the treatment of mental illness. However, until recently, research into the possibility of enriching people’s lives through psychedelic experiences has stagnated. Over the past few years, there has been a resurgence of clinical research using psychedelic drugs on volunteers. Today, it is recognized that their use has a positive effect on therapy and personal growth. A list of planned, ongoing and completed clinical trials using psychedelics can be found on the clinicaltrials.gov website; search for the words “psylocybin” or “psychedelic.”

The renewed interest in human research on these drugs is good news for those interested in the psychological and psychotherapy aspects of psychedelic substances, as well as for those interested in non-medical uses of these substances, including their obvious value in self-discovery, increased creativity, improved learning, problem-solving, and spirituality. It is likely that these properties of psychedelic substances will be studied in more detail and, possibly, in the near future, these drugs will find new applications. published

P.S. And remember, just changing our consumption – together we change the world!

Source: theoryandpractice.ru