As your eyes close, a kaleidoscopic vision of pattern, color, and sense of deep meaning engulfs your entire field of experience. Thirty minutes ago you were given a controlled dose of a highly potent, and highly illegal, hallucinogenic compound—all in the name of science. Months from now, you will say that this was one of the most profound experiences of your life . You have joined a small but growing number of human subjects participating in an exciting new wave of research. The aim of this work is to understand how an infamous class of mind-altering substances—the psychedelics—may actually be a powerful tool for treating certain forms of psychological suffering.
Psychedelics are a special class of substances known for the vivid perceptual and cognitive changes they induce. Most are classified as Schedule I controlled substances. Legally, this means the U.S. federal government believes they have a high potential for abuse, no currently accepted medical use, and are unsafe to consume even under medical supervision. Despite this legal classification, a variety of psychedelics are currently being studied in laboratory and clinical settings. The results of this research suggest that they are non-toxic, pose no significant risk of dependence, and show great promise in treating a variety of psychiatric ailments . But how do they actually exert their effects in the brain?
What do psychedelics actually do?
The classical psychedelics include, psilocybin, an organic molecule found in a variety of fungi (“magic mushrooms”), lysergic acid diethylamide (LSD), originally synthesized from components of a wheat fungus, and dimethyltryptamine (DMT), an especially potent psychedelic produced by many plant species . The chemical structures of these compounds resemble serotonin, an important chemical messenger in the nervous system (Figure 1). One of their primary effects is to stimulate neurons in the brain that are naturally responsive to serotonin. These serotonin-sensitive brain cells are widespread in the wrinkly outer layer of the brain known as the cerebral cortex. This structure is disproportionately large in humans compared to other mammals, and is widely believed to endow us with many of our higher cognitive abilities.
Figure 1 ~ Psychedelic compounds such as psilocybin, dimethyltryptamine (DMT) and lysergic acid diethylamide (LSD) have chemical structures that resemble the neurotransmitter serotonin. This structural similarity to serotonin allows them to stimulate serotonin-sensitive neurons in the brain. (Source: ChemDraw)
Although psychedelics typically share similar chemical properties, the effective doses, routes of administration, and duration of their effects vary dramatically. The subjective effects also depend strongly on a person’s environment and expectations . At low to moderate doses these typically include mild to moderate distortions in cognition and sensory perception. At higher doses, profound, life-altering experiences are commonly reported, often described as having a mystical or transcendental character .
Unlike psychedelics, drugs of abuse such as cocaine, methamphetamine, and nicotine strongly stimulate the brain’s dopamine system (Figure 2), which is critical for their habit-forming potential. The ability of psychedelics to act primarily on the serotonin system is thought to be important for their unique subjective effects and negligible habit-forming potential. Preventing their ability to stimulate serotonin-sensitive neurons also prevents their hallucinogenic effects . But what is going on in the brain as a whole during the psychedelic experience? In just the past few years, the tools of modern neuroscience have allowed researchers to begin to answer this question.
Psilocybin: effects on brain activity and conscious experience
Neuroscientists have recently studied the effects of psilocybin on the brain activity of healthy human participants . They found that psilocybin caused changes in activity across the entire cerebral cortex. These changes were especially pronounced in areas of the cerebral cortex that make up the default-mode network. The default-mode network is composed of a group of brain areas that is most active when we are not actively engaged in a task, and is thought to be important for aspects of cognition such as introspection, mind-wandering, and self-referential thought.
Another study using functional brain imaging also found psilocybin-induced changes in brain activity . In particular, they observed that psilocybin led to decreased activity in several brain regions, with some of the largest decreases in default-mode areas like the medial prefrontal cortex and posterior cingulate cortex (Figure 2). These same brain regions harbor many of the serotonin-sensitive neurons that psychedelics interact with, and show increased activity during self-related thinking under normal conditions. Could one of the major effects of psilocybin and other psychedelics be to decrease activity in certain brain regions, thereby changing the very sense of self that typically frames our everyday conscious experience?
Figure 2 ~ Illustration of the dopamine and serotonin pathways in the human brain. Many drugs of abuse act directly on specific parts of the dopamine pathway, whereas psychedelics act primarily through the serotonin pathway. Note that the serotonin pathway extends throughout the entire cerebral cortex, including default-mode areas such as the medial prefrontal cortex and posterior cingulate cortex, highlighted in pink. Figure by Brian Chow.
Intriguingly, default-mode areas also become less active in other altered states of consciousness, such as meditation . Indeed, people often use similar language to describe the psychedelic experience and non-ordinary states of consciousness like meditation and sensory deprivation [8,9]. These include experiences of depersonalization, frequently verbalized in terms of “ego disintegration,” “boundlessness,” or the feeling that all things are intimately connected . Meditation and sensory deprivation have also been implicated as treatments for depression and anxiety , which is an area where psychedelics like psilocybin show great promise.
Psychedelics (mainly LSD) were originally studied in the mid-twentieth century, and had shown promise in treating alcoholism and end-of-life anxiety . The original impetus for this research came in part from psychiatrists’ own experience with these substances, and the idea that they might work by allowing patients to see their condition from a new perspective . But after passage of the US Controlled Substances Act in 1970, research halted. In the past several years, however, the potential therapeutic applications of psychedelics have once again become an active area of research.
Psilocybin was recently been given to healthy volunteers in order to study its acute and long-lasting effects. The main finding was that, in most people, psilocybin could induce highly profound, “mystical-type” experiences . In interviews and questionnaires administered after these sessions, participants rated their psilocybin experiences high in qualities such as ineffability (difficult to describe in words), unity (feeling that all things are connected), and having a deeply felt positive mood. Two months after these sessions, the vast majority of participants rated their psilocybin experience as one of the top five most meaningful experiences of their life and as having increased their sense of well-being and life satisfaction. To help put things into clearer perspective, participants sometimes compared the significance of their experience to the death of a parent, or birth of their first child.
Psilocybin has also been administered to terminally ill cancer patients with the hope of alleviating their psychological distress. For many people, learning of a terminal diagnosis can lead to debilitating depression and anxiety. An initial study demonstrated that psilocybin could be safely administered to such patients without inducing adverse effects . Cancer patients in a more recent study at NYU Medical School have seen dramatic and long-lasting reductions in depression and anxiety. Remarkably, these effects were achieved after just a single dose of psilocybin , and it is astounding to hear personal testimonies from patients: “I don’t think I’ve experienced—ever—the gratitude that I felt. Gratitude for what? It was just gratitude. I don’t like to talk about it, because it’s really beyond words.” 
Figure 3 ~ Dried specimens of Psilocybe cubensis, one of many species of “magic mushrooms.” Mushrooms belonging to the genus Psilocybe contain psychoactive compounds such as psilocybin, which has recently been studied for its potential therapeutic uses. (Photo by Erik Fenderson: http://commons.wikimedia.org/wiki/File:Dried_Cubensis.jpg)
A major theme of this research so far is that psilocybin can, under appropriate conditions, reliably induce profound and potentially life-altering experiences; it seems to be able to change brain activity in ways that radically shift our sense of self, reinforcing the original intuition that psychedelics may help reframe a person’s typical thought patterns. “Cognitive reframing” is a common strategy in traditional psychotherapy, and psychedelics may provide a means for kick-starting the reframing process. In the words of one researcher, “individuals transcend their primary identification with their bodies and experience ego-free states [during the psychedelic experience]… and return with a new perspective and profound acceptance .” In this spirit, pilot studies investigating the potential use of psilocybin as an addiction therapy aid have been very encouraging, with success rates as high as 80% in an initial smoking cessation study, and larger studies currently underway .
Despite a variety of promising results, researchers urge extreme caution. They stress that this area of research in its infancy, and that experiments have been conducted under carefully controlled, comfortable, and supervised conditions. Disturbing psychedelic experiences (“bad trips”) have been reported by recreational users , and participants in psychedelic research are carefully screened for mental health issues before being selected. Nonetheless, there is optimism that psychedelics may one day become part of the legal psychiatric toolkit. More research is sorely needed, and some researchers have recommended that the federal government reclassify these substances in order to facilitate future efforts . No matter what the future holds for the place of these substances in society, the work currently being done suggests that, for some people, the psychedelic experience may be well worth the trip.
Nick Jikomes is a Ph.D. candidate in the Harvard University Program in Neuroscience
Follow @njikomes on Twitter
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For further information
 Psychoactive Basics. Erowid. https://www.erowid.org/psychoactives/basics/basics.shtml
 Harris, Sam. (2011, July 4). Drugs and the Meaning of Life.
 Nichols, David (2011, January 6). David Nichols – Psychedelic Science.