The Doors of Perception: Without Psychedelics, Neuroscience Wouldn’t Exist
Science is gradually rehabilitating psychedelics—recent years have seen a renewed interest in experimental research on psilocybin and other psychoactive substances. It’s worth remembering how it all began: in the 1960s, experiments aimed at expanding consciousness became a treasure trove of new information for psychotherapists and neurobiologists. In particular, these studies revealed the role of serotonin in brain function—an insight that laid the foundation for all modern psychopharmacology.
From Behaviorism to Neurochemistry
In the mid-20th century, dominant theories in psychology and psychiatry held that mood, desires, emotions, memory, behavior, and personality were shaped by the environment, childhood experiences, and the interplay of reward, punishment, repression, and reinforcement of the subconscious mind, including psychosexual mechanisms. Brain activity was believed to be primarily electrical in nature. Until the 1940s and early 1950s, the idea that consciousness was influenced—or even determined—by chemicals produced in the brain was completely foreign to the medical community.
Key events that shifted these paradigms and gave rise to neurochemistry, neuropharmacology, and ultimately psychopharmacology as a scientific discipline centered around the discovery and study of the psychoactive effects of lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), psilocybin, and other psychedelic substances.
The Discovery of Serotonin’s Role
Perhaps the most important breakthrough in psychedelic research was identifying the role of serotonin in mental processes. The chemical structure of serotonin was determined in 1949, and it had been known since the late 1800s to be present in clotted blood, where it helps stop bleeding by causing blood vessels to constrict and promoting clot formation. In the early 1950s, serotonin was also discovered in brain tissue, suggesting a potential role in brain function and consciousness. This discovery was made independently by groups in the United States and in Edinburgh, Scotland, led by Sir John H. Gaddum.
Gaddum, a British pharmacologist, played a key role in early serotonin research. In 1953, he self-administered LSD four times to study its effects. These self-experiments, along with his lab work on LSD and serotonin, led Gaddum to be the first to propose a link between LSD and serotonin, suggesting that LSD’s psychedelic effects were due to its impact on serotonin function. His handwritten notes from a self-experiment with 86 micrograms of LSD on June 1, 1953, read:
“9:48 My hand looks strange, as if it’s a monstrous drawing of a hand, writhing until I focus on it. The color contrasts are amazing. I see what seems to be a more-than-real drawing, which feels quite odd—as if it belongs to someone else. Everything in the room is quite unstable.”
He continued: “Evidence of HT (serotonin) in certain parts of the brain may support the theory that the mental effects of lysergic acid diethylamide arise from interference with HT (serotonin).” Thus, Gaddum’s personal experience with LSD and scientific insight merged, sparking the birth of chemical neuroscience.
Serotonin, DMT, and the Birth of Psychopharmacology
Independently, D. Woolley and E. Shaw in New York also proposed that “the mental disturbances caused by lysergic acid diethylamide should be attributed to the acid’s interference with serotonin in the brain.” They noted that “Gaddum was also aware of the mental effects of LSD and serotonin’s action in the brain. We assumed he was thinking along the same lines as we were, about the relationship between serotonin and the mental disturbances caused by the substance.” Unlike Gaddum, there’s no evidence Woolley or Shaw took LSD themselves.
They later wrote: “These pharmacological discoveries indicate that serotonin plays an important role in mental processes, and that suppressing its action causes mental disorders. In other words, a lack of serotonin is the cause of the disorder. If a serotonin deficit in the central nervous system results from metabolic issues rather than drugs, similar mental disorders can be expected. Perhaps such a deficiency is responsible for naturally occurring illnesses… Thus, we propose: serotonin likely helps maintain normal mental processes; a metabolic serotonin deficiency may contribute to some mental disorders; serotonin or a long-acting derivative may alleviate mental disorders like schizophrenia.”
These early reports laid the groundwork for today’s research and the development of modern psychotherapeutic drugs, fueling a multi-billion-dollar pharmaceutical industry focused on altering serotonin and other neurotransmitters in the brain to treat mental illness.
DMT and the Expansion of Consciousness Research
DMT also had a major impact on our understanding of normal and extraordinary states of consciousness. In 1961, Nobel laureate Julius Axelrod discovered that mammalian tissue (rabbit lung) could synthesize DMT. This finding was thoroughly investigated in the early 1970s, when it was shown that human brain tissue obtained via biopsy could perform the same biotransformation. The discovery that human brain tissue could produce small amounts of DMT in the lab sparked intense debate about DMT’s possible role in human consciousness. However, analytical technology at the time was not sensitive or reliable enough to settle the question, and for nearly 30 years, the issue remained unresolved.
In 1999, Michael Thompson and colleagues at the Mayo Medical Institute in Rochester, Minnesota, using molecular biology techniques, discovered a human gene encoding the enzyme that synthesizes DMT from tryptamine. This finding reignited debate and strongly supported the hypothesis that endogenous DMT plays a key role in states such as euphoria, dreaming, creativity, near-death experiences, and more. The idea that DMT in mammalian tissue was merely an artifact was finally dismissed.
Psychedelics, Receptors, and the Diversity of Experience
Since Gaddum’s time, research on psychedelics, serotonin, and other neurotransmitters and their receptors has accelerated. Building on early theories about serotonin’s role in LSD pharmacology, in the 1980s Richard Glennon and colleagues at Virginia Commonwealth University’s School of Pharmacy were the first to identify the serotonin 2 receptor (now called 5-HT2A) as the main target for psychedelics like lysergamide, phenethylamine, and indolealkylamine. Over the next two decades, additional binding sites were discovered; today, more than 40 receptor sites for psychedelics are known. While 5-HT2A is still considered the primary receptor, researchers increasingly believe that activity at this site alone cannot explain all psychedelic effects.
It’s clear that the simultaneous action of psychedelics on many—or even all—of these 40+ receptor sites, with each psychedelic agent having a unique binding and activation profile (a pharmacological “fingerprint”), creates the wide range of subjective experiences these substances produce. Thus, while the term “psychedelic” is often used as a catch-all, these substances, though they may cause similar effects, do not produce identical experiences—something users readily report. The effects of LSD are quite different from those of mescaline, which differ from DMT, which differ from TMA-2, psilocybin, 2C-B, and so on.
Although laboratory (in vitro) and animal behavioral studies are commonly used to study these substances, these approaches often blur the qualitative, empirical differences between psychedelics—differences that humans can easily distinguish. Lab and animal data can supplement, but never replace, human experience, which is essential for understanding psychedelic effects.
Defining Psychedelics and Their Effects
The challenge of defining psychedelics and the experiences they produce is not new. As Alexander Shulgin said, “If there is confusion in choosing a term to describe the class of drugs we call [psychedelics], then agreeing on a description of their effects will lead to complete chaos.” One approach, proposed in the 1970s, was to define psychedelics as substances that mimic the effects of LSD. While this definition is circular, it placed the psychedelic experience at the center of the discussion. Lester Grinspoon and James Bakalar suggested: “A drug will be considered psychedelic or not depending on how much and in what way it resembles LSD; similarity should be judged by the drug’s cultural role and the range of its psychopharmacological effects. From this perspective, the group of psychedelic drugs has a well-defined center and a blurred periphery…”
From Molecules to Human Experience
Linking a drug’s molecular action to animal behavior and human experience remains an enticing but not fully realized goal. Much of the progress in this field is thanks to Alexander Shulgin, who developed, synthesized, and characterized over 200 new psychedelic substances in his private lab. Shulgin’s compounds have been used by scientists worldwide to study receptor binding and activation, for computer modeling and receptor mapping, for investigating neuronal electrical activity, animal behavior, and more. Shulgin’s work also greatly enriched the diversity of human psychedelic experience.
From the literature and other sources, it’s clear that most modern research on neurotransmitters and drugs affecting brain function can be traced back to experiments and studies on the mechanisms of LSD, DMT, and other psychedelics.
The Rise of Psychopharmacology
In light of these neurochemical discoveries, psychology and psychiatry had to revise their assumptions about the origins and nature of consciousness and mental illness. It became necessary to incorporate neurobiological observations into models of mental functioning. Neurochemistry and neuropharmacology began to dominate research into consciousness and the treatment of mental illness by the late 1950s and 1960s. For example, the use of psychoactive drugs based on experimental neuropharmacological discoveries became a standard approach in psychological treatment, giving rise to psychopharmacology as a medical and scientific discipline. While there is still much room for improvement, the effectiveness of these drugs has undoubtedly saved countless lives.
Modern Research and the Psychedelic Renaissance
Although clinical research on psychedelics in humans was temporarily halted in the late 1960s and 1970s, studies of their chemistry, pharmacology, and neurobiology continued. In scientific circles, research on the chemical synthesis and pharmacology of psychedelics was centered in the labs of Richard Glennon and David Nichols at Purdue University, George Aghajanian at Yale, and many others who used animal models to study these substances.
Today, academic research on psychedelics is conducted in various pharmaceutical and medical institutes, as well as in departments of medicinal chemistry, neurology, pharmacology, psychology, and psychiatry. Students interested in this field can find research opportunities worldwide by searching scientific literature databases like PubMed.
For those seriously interested in psychedelic research, especially involving human studies, a PhD or MD is essential for academic or clinical research. Several years of postdoctoral training can eventually lead to a principal investigator role in basic science or clinical trials. After earning a bachelor’s degree and entering graduate school, opportunities in this field expand, whether as a team member in university research, a pharmaceutical company, the National Institutes of Health, or a private research foundation.
The Future of Psychedelic Science
As described above, psychedelics have been used for decades to answer mechanistic questions about receptors, neural processes, and animal behavior. Research with psychedelics provides deeper insight into brain function and continues to influence psychopharmacology and the development of drugs for mental illness. Until recently, studies on the potential for psychedelics to enrich human life had stagnated. In the past few years, there has been a revival of clinical research on psychedelics in volunteers. Today, their use is increasingly recognized as beneficial for therapy and personal growth. A list of planned, ongoing, and completed clinical trials with psychedelics can be found at clinicaltrials.gov; search for “psilocybin” or “psychedelic.”
This renewed interest in human research is good news for those interested in the psychological and psychotherapeutic aspects of psychedelics, as well as for those interested in non-medical uses, including their value for self-discovery, creativity, learning, problem-solving, and spirituality. It’s likely that these properties will be studied in more detail and, perhaps, new applications for psychedelics will be found in the near future.