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    Can psychedelic drugs, once banned, help relieve mental illness?

    Decades after most hallucinogens were outlawed as dangerous, researchers are using them to treat disorders like PTSD, depression, and addiction. Still a mystery: How they actually work.

    Jesse Gould hikes in the Amazon rainforest in Peru.
    Jesse Gould hikes in the Amazon rainforest in Peru.
    Courtesy: Jeremy Lock

    For a 26-year-old international finance analyst who had never even tried pot, sitting in a Peruvian jungle downing a drink derived from a psychedelic plant was a strange trip even before the hallucinations kicked in.

    Jesse Gould was that desperate.

    “I’d miss work because of panic attacks,” the Army veteran says about the post-traumatic stress disorder (PTSD) that engulfed him after three tours in Afghanistan. “I would wake up with dread in my chest. I was self-medicating with alcohol. The anxiety would transform into severe depression and borderline manic behavior.”

    Having seen fellow veterans suffer severe side effects from SSRIs (selective serotonin reuptake inhibitors) — a class of antidepressants often used to treat PTSD that doctors had recommended to him — Gould researched an alternative that is not legally available in the United States: ayahuasca (“eye-ah-WAH-ska”), a plant-based psychedelic often used in South America to treat mental ailments. In February 2017, he traveled from his home in Tampa, Florida, to Peru to try it.

    Gould went through four rounds of treatment, experiencing hallucinations that began as disturbing but eventually calmed him on a fundamental level. “It was almost like this hand pulled me out of the chaos and into this completely peaceful sort of environment,” Gould recalls. “It was almost a bootcamp for dealing with my anxiety and unprocessed trauma. I was able to let go.”

    Today, dozens of academic medical centers in the United States are conducting clinical trials to determine the efficacy and safety of psychedelic drug treatment. The trials use drugs that are banned or severely restricted for therapeutic use — including psilocybin (an element in “magic mushrooms”), MDMA (3,4-methylenedioxy-methamphetamine, also known by its street name, ecstasy), LSD, and ketamine — to address such disorders as PTSD, depression, drug and alcohol addiction, smoking, eating disorders, prolonged grief, cluster headaches, and health worker burnout.

    The research is fueled by changing attitudes among government regulators and the public. In the 1970s the federal government classified psychedelics as Schedule 1 substances, making them illegal to possess even for research, as the result of abuse and the social stigma that grew in response to the counterculture “turn on, tune in, drop out” mindset promulgated by LSD advocates.

    “Nobody was doing any clinical research with these drugs between the early 1970s until about 2000,” says Albert Garcia-Romeu, PhD, assistant professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, who researches psilocybin.

    Over the years, however, it became clear that many people suffering from mental disorders such as PTSD do not respond sufficiently to standard drug-and-talk therapy. Meanwhile, evolving norms about nontraditional healing practices, including the use of marijuana for medicinal purposes, opened the way for reconsideration of psychedelics. In 2019 the U.S. Food and Drug Administration (FDA) approved a form of ketamine (a hallucinogenic) to treat depression, and the FDA appears to be considering approval of the psychedelic drugs psilocybin and MDMA for treatment of PTSD and depression. Also over the past few years, voters in Oregon and Colorado have passed measures to allow psilocybin for therapeutic use; other states are considering similar moves.

    How they work

    Ask the top researchers how psychedelic drugs alleviate mental disorders, and you get answers like, “we don’t really know” and “it remains a mystery.”

    Some hypotheses suggest  that psychedelics enhance neural plasticity and that they can disrupt normal patterns of brain activity. Those mechanisms might help to break down neurological loops that trap people in destructive patterns of thinking, like being stuck in a traffic circle with no exits. Think of someone who has developed a depression-and-reward cycle that compels them to drink alcohol, or who keeps reimagining a traumatic experience (such as a violent assault) and feeling the fear afresh each time. 

    “These [harmful] mental patterns involve repetition and rigidity,” notes Greg Fonzo, PhD, co-director of the Center for Psychedelic Research and Therapy at The University of Texas at Austin Dell Medical School. “People get stuck in these patterns. The hypothesis is that these drugs help shake people out of these repetitive mental patterns.”

    The shakeup is both psychological and biological.

    Patients who’ve used psychedelics describe a range of acute reactions, both positive and negative: heightened perceptions, elevated mood, fright, disconnection from their sense of self, and mystical experiences. Some report hallucinations, such as seeing kaleidoscopic color swirls, feeling literally connected with nature, and talking with deceased loved ones.

    “I had these images: One was a calm jungle, one was a beach,” says Gould. He even felt a cool breeze. “It was just the most peaceful thing that you can possibly imagine.”

    Many people come out of the high (which typically lasts four or more hours with psilocybin and MDMA, and longer with LSD) with fundamentally new perspectives about themselves and the meaning of their lives. Gould emerged with a newfound confidence and clear sense of purpose to his life.

    “The experience was almost like showing me that spot in my brain where I didn’t have to latch onto” his worries and fears, he recalls.

    Researchers are trying to pin down those spots of the brain that psychedelics affect, and how. That includes looking at changes in and interactions between the prefrontal cortex and the hippocampus, which play key roles in various behavioral and cognitive functions, including memory.

    “The novelty of the [psychedelic] experience produces this kind of burst of plasticity,” says Joshua Siegel, PhD, a postdoctoral research fellow in psychiatry at Washington University School of Medicine in St. Louis. “It doesn’t necessarily cure psychiatric illness, but it enables adaptation.”

    In an experiment at the University of South Florida, researchers taught mice to fear a certain tone because it was accompanied by an electric shock, then removed the shock to see how long it would take the mice to stop reacting in fear to the tone. Mice who were given psilocybin unlearned the fear significantly faster than the other mice, and dissections showed that the drug had accelerated the growth of neural connections in those adaptive mice.

    In human trials, researchers are peering into the brain in real time, using functional MRI scans to get images of neural activity during and after psychedelic dosing sessions. In psilocybin trials, researchers at the University of Washington are studying brain activity in health workers suffering burnout, while researchers at Dell Med are examining people suffering prolonged grief over the deaths of family members who died in military duty. Several studies, such as this one at Johns Hopkins, have found that psilocybin helps to regulate how various regions of the brain turn on and off, and how those regions communicate with each other.

    “Psychedelics are altering the pattern of communication between brain areas,” Siegel says.

    Holistic approach

    However the drugs work, many researchers believe the impact is probably not just from the drugs. Psychedelic treatments usually involve preparation before the dosing sessions and psychotherapy after the experience. The theory is that the eradication of a harmful thought loop isn’t sufficient for recovery; it could be replaced by another harmful loop.

    “It’s not just that you take a pill,” says Boris D. Heifets, MD, PhD, assistant professor of anesthesiology, perioperative and pain medicine at Stanford Medicine, in California.

    The strategy is to build on the opportunity that psychedelics appear to provide. For example, a study of heavy drinkers, run by several academic medical centers, found that “psilocybin administered in combination with psychotherapy produced robust decreases in the percentage of heavy drinking days” compared with participants who got a placebo and psychotherapy.

    “The idea is that the psychedelic is enhancing the effects of, or synergizing with, the psychotherapy,” says Christopher J. Pittenger, MD, PhD, director of the Clinical Neuroscience Research Unit at Yale School of Medicine, in Connecticut. “If you give cognitive behavioral therapy in the window during which plasticity is enhanced after a psychedelic dose, then perhaps that would enhance the efficacy of therapy.”

    The need for a high level of hands-on therapeutic attention highlights the drawbacks of drug-induced psychedelic episodes: Their effects can be unpredictable and are potentially dangerous without proper support, and thus require significant time to administer by trained staff. 

    People undergoing psychedelic therapies are typically monitored before, during, and after treatment. Some have reported distressing experiences while on the drugs or after, including paranoia, fear, and severe anxiety. (Others, who have used psychedelics without medical supervision, have reported more severe emotional disturbances afterwards, such as mania and depression.) Gould says his first two rounds with ayahuasca set off discomfort, anxiety, disorientation, regurgitation, sweating, and “get me out of here kind of thoughts.” But he had invested so much time, money, and faith (based on his research) that he stuck with it.

    Such risks are among the reasons that psychedelic therapy, as conducted in trials, is “resource intensive” in terms of time and trained staff, Pittenger notes. It takes hours of counseling up front (which includes discussing objectives, managing expectations, and preparing for the psychedelic experience itself), about eight hours on the day of the dosing session (allowing for preparation, supervision during the experience, and debriefing after), and hours of follow-up therapy. Patients often go through several dosing sessions.

    “We try to get insights from your psychedelic experience and apply them to your life,” says Heifets, who is also an assistant professor at Stanford Medicine’s Wu Tsai Neurosciences Institute.

    Gould got just a little of that during his ayahuasca treatments in Peru. There were talk circles with other patients reflecting on their psychedelic experiences, and advice about diet and meditation practices moving forward. Seeing both the benefits of the treatment and the value of structured support, Gould launched the nonprofit Heroic Hearts Project, which provides supervised, multi-day psychedelic treatments for military veterans and their families. The treatments are done outside the United States. For example, Dell Med partners with the Heroic Hearts Project to carry out a long-term grief observational study, in Mexico, for families of deceased veterans.

    Researchers caution that there’s much to be learned about how and for whom the drugs work. If any of the drugs are approved for medical treatment in the United States, no one knows how much, if any, would be covered by health insurance. Multi-day retreats for psilocybin treatment in Jamaica and Mexico typically cost $4,000 or more. The cost in the U.S. medical system would probably be higher because of all the staff time and counseling required, says Pittenger at Yale.

    “If these cost tens of thousands of dollars, then they’ll become boutique treatments for the wealthy,” he says. “We as a profession will fail precisely the people who most need our help. That would be tragic.”

    Those are the people whom psychedelic drug advocates want to reach.

    “Most of the veterans that come to us [at Heroic Hearts] have run out of options,” Gould says. “They have tried medications and therapy to limited effect. They are struggling and losing hope.

    “These veterans hear stories of people who served who not only were healed of their trauma [through psychedelic therapy] but also are thriving in life.”