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Psychedelic drugs conjure images of tie-dyed tee shirts, Woodstock, and Vietnam War protests. While early research into the properties of drugs like psilocybin (magic mushrooms) and lysergic acid diethylamide (LSD) during the middle of the 20th century suggested therapeutic potential for diverse mental health conditions, their role in the 1960s anti-war and counterculture movement made them suspect by law enforcement. Not long after American psychologist Timothy Leary called for people to “turn on, tune in, and drop out,” endorsing the regular use of psychedelic drugs for health and well-being, the federal Controlled Substances Act classified them as highly dangerous Schedule 1 compounds, or drugs with “no currently accepted medical use and a high potential for abuse.”
“Initially, psychedelics showed quite a lot of promise for treating a wide range of mental health conditions—in particular, addiction and post-traumatic stress disorder (PTSD),” says Anil Seth, co-director of the Sackler Centre for Consciousness Science at the University of Sussex in the United Kingdom. “There’s long been a blame game going regarding what led to these drugs being outlawed, mostly focusing on people like Timothy Leary promoting indiscriminate use of what we know are quite powerful drugs. But the end result was that, despite their promise, it became nearly impossible for anyone to do any research at all on them.”
Over the past decade, however, there has been a revival of psychopharmacology and neuroscience research into the effects of psychedelic drugs. In fact, despite continuing legal barriers and funding challenges involved with using these banned drugs in research studies—many researchers wait years for Food and Drug Administration approvals and require funding from non-governmental agencies to move forward—several unique research centers, including the Centre for Psychedelic Research at Imperial College London and Johns Hopkins University’s Center for Psychedelics and Consciousness Research, are now actively studying LSD, psilocybin, and dimethyltryptamine (DMT), from both basic science and clinical perspectives.
“People often come out of a psychedelic experience and say it was one of those most remarkable things they’ve ever experienced—that the experience led to creative insights and improvements in self-identity and mood,” says Matthew Johnson, a researcher at the Center for Psychedelics and Consciousness Research. “When people consistently say things like that, you start to ask yourself what the heck is going on—you want to understand why.”
Certainly, psychedelic drugs have distinctive psychoactive effects, including visual and other sensory distortions, hallucinations, changes in mood, and alterations in other cognitive processes like working memory and executive function. What’s more, psychedelic “trips” are remarkably subjective experiences. No two people report the same experience on these drugs—nor do single individuals say they have had the same experience during two different exposures.
These remarkable experiences, said David Nutt, director of neuropsychopharmacology at Imperial College London, have led scientists to ask fundamental questions about how they work.
“This resurgence really all started with some of us asking a quite simple question; now that neuroscience had advanced to a point where we could take a closer look at the brain,” says Nutt. “What is the nature of the psychedelic state? What are these drugs doing to the brain?”
Robin Carhart-Harris, head of the Centre for Psychedelic Research at Imperial College London, observes that much has been written about the psychedelic experience, especially since many of these substances, like the naturally occurring peyote and mescaline, have been used in spiritual practices for centuries. But, like Nutt, he believes the biggest mystery remains what psychedelic drugs do in the brain that lead to such powerful perceptual and cognitive effects. Animal work suggests these drugs stimulate serotonin 2A receptors (5-HT2As), resulting in the growth of dendritic branches and an increase in synaptic connections. Neuroimaging work across several laboratories suggests that their use also has a profound “disorganizing” effect on brain networks, including the default mode network, sometimes referred to as the brain’s resting state network.
“There’s something about the 5-HT2A that helps to structure brain activity—and psilocybin disrupts normal patterns of activity in brain networks,” says Nutt. “When we saw it, it all made perfect sense. We could explain hallucinations by a disruption in the coordination of the visual system. We could explain the out-of-body experiences by the disruption of the default mode network. By looking at how these networks were altered, we really could explain almost all of things people report experiencing through these insights into brain function.”
Carhart-Harris says such studies can also offer greater insights into how the brain is organized normally. As these large-scale networks “temporarily disintegrate” in response to the drugs, scientists can learn more about how the brain facilitates normal cognition, including consciousness. Christof Koch, chief scientist of the MindScope Program at the Allen Institute for Brain Sciences, and a leading expert in consciousness, agrees. He hopes to use psychedelics in living brain tissue samples to see changes in the cells.
“New explorations of higher states of consciousness are usually only accessible if your participant has engaged in 20 years of meditation or prayer—and very few people get there,” says Koch. “But psychedelics offer the opportunity to study these changes in the cells reliably at the molecular level. It may help us understand what is required from a neurobiological standpoint to achieve different states of consciousness.”
For his part, Seth hopes to use psychedelics to better understand perception. Sensory distortions are a hallmark response to these drugs, and the extraordinary vividness of such distortions may provide new insights into how the perceptual system works. His work with Carhart-Harris has shown that the disorganization of networks caused by psychedelics has a high degree of randomness—and that information flow decreases between brain regions that normally communicate with one another.
“The take-home, basically, from these studies is that there is a large change in the global properties of brain dynamics which reflect increased disorganization and a lack of structure,” Seth explains. “The brain areas are becoming more random in their activity and speaking to each other less. The more we can understand about this, the more insights we could gain into what has gone wrong in psychosis or other psychiatric conditions that result in hallucinations or other perceptual defects.”
The study of psychedelics may offer a window into other fascinating phenomena as well. For example, the Johns Hopkins group recently published a study looking at feelings of interacting while using DMT with a compelling presence of another form of consciousness, such as a spiritual entity like God, an angel, a ghost, or even an alien.
“These experiences are rated as extremely significant by those who have them and result in enduring positive effects regarding their attitudes about life and self, mood, and social relationships,” says Ethan Hurwitz, a doctoral student at the University of California San Diego and a member of the Johns Hopkins Center for Psychedelics and Consciousness Research who worked on this study. “The fact that DMT can reliably elicit these kinds of autonomous entity experiences that yield these kinds of positive effects means they could show promise as a potential adjunct to traditional therapies for mood and behavior problems.”
Promise as a Therapeutic
Some of the earliest work on psychedelics, in fact, hinted at their promise for treating depression. Certainly, people often report increased well-being and improved mood after a recreational psychedelic experience—but unlike other euphoria-causing drugs, those feelings can last for days or even weeks after “a trip.” Charles Raison, a psychiatrist at the University of Wisconsin Madison, says, given the personal and societal costs of treatment-resistant depression, it is important to look at psychedelics’ potential as a therapeutic.
“Typical antidepressants don’t work for everyone,” he says. “And psychedelics have these powerful mental health benefits which probably work by very different mechanisms than drugs like selective serotonin reuptake inhibitors (SSRIs).”
Certainly, the basic science work suggests that is the case. Nutt and colleagues demonstrated that psilocybin reduced activity in the subgenual cingulate cortex, a region of the brain implicated in depression.
“This region is one of the driving nodes of depression,” Nutt explains. “And other work has shown that a necessary feature of antidepressant therapies is the ability to switch down activity in this area. When you couple that with the profound changes in the default mode—and there is evidence that overconnectivity in this network leads to depressive ruminations—you see why these drugs may have therapeutic effects.”
Several studies have now shown just that. Recently, the Johns Hopkins group published the first randomized controlled trial of psilocybin-assisted therapy—the drug is administered in conjunction with talk therapy—in patients with major depressive disorder. Frederick Barrett, a researcher at the Center for Psychedelics and Consciousness Research, says the study showed an “impressive” positive effect in patients, with more than 70 percent showing a significant response within one month.
“The psychedelic experience is very different than what people experience in waking consciousness,” he explains. “But when people have these experiences, especially when it’s supported by psychotherapy, they may see what is behind their depression and confront those things so they can move forward.”
Johnson, who also worked on the trial, says he sees psilocybin-assisted therapy as a way to “bring psychology back into psychiatry.”
“Everyone is depressed for different reasons,” Johnson says. “And the psychedelic experience can help you get to the heart of your own issues, which when you are guided by a mental health professional, seems to have really strong therapeutic effects.”
Despite such promise, many scientists urge caution. Jeffrey Lieberman, chairman of psychiatry at Columbia University, says that he has concerns that there has not been enough research looking at psychedelics’ safety. There are risks of psychosis in some patients, as well as cardiovascular issues.
“I don’t want to throw cold water on this reemergence because we could certainly use more treatments in depression,” he says. “But there are questions we need to answer: What is their comparative pharmacology (how these drugs compare to other psychedelics or antidepressant medications)? What is their duration of action? What happens when you do multiple dosing? What are the long-term effects to the brain? We don’t know yet.”
Raison wholeheartedly agrees. With two to three percent of individuals in survey studies reporting worse outcomes after taking psychedelics, the answers to these questions matter, and matter greatly.
“The research suggests that there will be a group of people who will not benefit from these agents,” he says. “It’s important we know who they are—who will benefit most and who may actually be harmed from their use—before we start giving it to people who are struggling with their mental health.”
As researchers start to consider the potential of psychedelic treatment beyond depression (some suggest it will have beneficial effects for a host of conditions ranging from drug addiction to PTSD to Alzheimer’s disease), these safety issues will become even more important. And, to add to the mix, Joseph Barnby, a psychopharmacologist at King’s College London, also said he has concerns about the lack of active placebo in both current and future clinical trials.
“In drug trials, you want to be blinded so neither you nor the study participant knows whether they received the drug, so you are not subject to expectancy effects,” he says. “With psychedelics, you have such a profound shift in the way you experience sensory information, it’s hard to blind people to whether someone has received the drug or not. The effects we see could just be placebo—and, as different trials continue to move forward, that’s something we need to carefully consider.”
Microdosing and the Future
Psychedelics also have strong reputation as a performance enhancer. Many popular musicians, artists, and tech wunderkinds have stated that microdosing—using small doses to avoid large-scale effects—can promote well-being, creativity, and productivity. Certainly, several survey studies have shown that people who microdose report these kinds of positive effects. But while there may be potential there, Carhart-Harris says that full-scale clinical trials are necessary to see whether results hold up.
“There is now a cultural phenomenon around microdosing, particularly in Silicon Valley, but the jury is still out on the evidence,” he says. “There’s been a lot of enthusiastic anecdotal reporting, but the evidence is lacking. Most of what we are seeing in our own lab suggests the effect is driven by positive expectations—it’s a placebo effect. But we need more thorough studies to know.”
That work, as well as the work regarding safety, will hopefully come sooner rather than later. With some states considering legalizing or decriminalizing certain psychedelic substances— Oregon recently became the first state to legalize psilocybin—it’s expected that, as with marijuana, recreational use will likely grow. Barrett says while he is enthusiastic about the clinical potential of these drugs, it’s important for people to know they are not a mental health or performance panacea—and there are significant risks to their use. That’s one of the reasons why he is such a proponent of psychedelic-assisted therapy, as opposed to patients taking these sorts of mind-altering drugs on their own.
“I don’t think anyone should be going to jail for using these drugs. But that doesn’t mean they don’t have powerful effects—and that people won’t get into trouble using them in unsafe conditions,” he says. “I believe the medicalization of these compounds will truly lead to a lot of people being healed if the larger studies replicate and confirm the clinical findings we have now. But people should proceed with caution.”
Seth concurs: “Psychedelics aren’t a magic bullet—and with the boosterism surrounding these drugs at the moment, especially in Silicon Valley, I worry that people might go too far. But, that said, if psychedelics are treated with respect, there is a lot of potential for both basic science and clinical practice. So, there’s a moral, ethical, and scientific obligation to explore these opportunities as far as we can. Let’s follow the evidence and see where it takes us.”
This article first appeared in the Winter 2021 issue of our Cerebrum magazine. Click the cover for the full e-magazine.