Some of the first pieces of knowledge of how psychedelics affect perception and benefit mental health date back to the late 1800s. Significant research was spurred by the synthesis of lysergic acid diethylamide (LSD) in 1938. The mid-20th century saw a range of clinical studies of LSD and other psychedelics, including psilocybin—the active compound in “magic mushrooms”—and their use as treatments in psychiatry in the U.S. and Europe.
Director, Canadian Centre for Psychedelic Science
But in the late 1960s and early 1970s, the increased use of psychedelics as recreational drugs and concerns about safety and potential for abuse led to their prohibition. The U.S. government even declared that psychedelics had no potential for use as therapeutics. As a result, psychedelics remained in a research purgatory for decades until a handful of scientists began revisiting their potential in the early 2000s. Today, there are no less than 130 clinical trials being conducted worldwide on potential therapeutic uses of psychedelics, although most are in early stages. Psilocybin is the most studied of a range of a range of drugs that includes LSD, ketamine, and methylenedioxymethamphetamine (MDMA), among others. The bulk of research centers on their use for mental health treatments such as major depressive disorder, post-traumatic stress syndrome (PTSD), anxiety, and substance abuse, with other studies focused on neurological disorders such as Parkinson’s disease.
The resurgence of interest in these drugs is likely influenced by shifting public opinion of psychedelics and ongoing efforts to legalize, or at least decriminalize, the use of psilocybin. Australia became the first country to officially recognize psilocybin as a medicine in July 2023. In the U.S., Oregon was the first in 2020, followed by Colorado in 2022, to enact laws that allow the supervised use of psilocybin for therapeutic purposes.
“Public interest in psychedelics has increased, perhaps exponentially,” said Rotem Petranker, director of the Canadian Centre for Psychedelic Science, whose early research in the 2000s focused on mindfulness. “Psychedelics was always interesting to me, but I never thought that the moment would come when it would be a legitimate research interest.”
Professor
Washington University
Leading research institutions have now made significant commitments to psychedelic inquiry, including the Johns Hopkins Center for Psychedelic and Consciousness Research, the U.K.’s Imperial Centre for Psychedelic Research, and the University of California, Berkeley Center for the Science of Psychedelics.
Ginger Nicol, MD, a clinical investigator and professor of psychology at Washington University (WashU), St. Louis, sees a couple of other factors influencing this surge in research. “Psychedelics offer so much hope and promise because they work so fast and they have such a profound effect,” she noted, “and the pandemic really brought it into full relief and showed us just how mental health is impacting all people.”
How psychedelics work
Psychedelics like psilocybin work on the brain primarily by interacting with the serotonin system, particularly the 5-HT2A receptor. Once in the body, psilocybin is converted into psilocin, which closely resembles serotonin. Psilocin binds to 5-HT2A receptors in areas of the brain such as the prefrontal cortex, which is a center of cognition, mood, and perception. It enhances communication in the brain between regions that typically do not communicate as much. It also suppresses the default mode network (DMN) in the brain, which was discovered ins 2001 by Nicol’s colleague at WashU, neuroimaging expert Marcus Raichle, MD. The DMN is a group of regions in the brain that are most active when the brain is at rest. Research suggests that DMN dysfunction may lie at the heart of a number of mental health conditions.
In this way, psychedelics lead to a state of neuroplasticity, which is what essentially allows the brain to grow and form new connections. Research by Nicol and colleagues sought to better understand the differences in brain activity when a person has and has not taken psilocybin. To do this, they recruited seven healthy individuals between the ages of 18 and 45 and dosed them with 25 mg psilocybin or 40 mg methylphenidate (brand name Ritalin; used as a control drug). The participants underwent magnetic resonance imaging (MRI) scans during both drug and non-drug sessions. The images showed that the psychedelics desynchronize brain activity both regionally and globally.
“We actually saw changes that give us an indication that this change might be one of the mechanisms by which psilocybin helps people with depression,” Nicol noted.
Significantly, their research showed that after a person took the psychedelic, the brain connectivity changes persisted for 3–4 weeks after dosing. This finding suggests potential for a longer therapeutic window.
Assistant Professor
University of Michigan
These findings were echoed by research from the University of Michigan (UM), conducted in the lab of Omar Ahmed, PhD, an assistant professor of psychology. The researchers used microdoses of the drug 25CN-NBOH, a psychedelic known for being a highly selective agonists of the serotonin 5-HT2A receptor. The UM team evaluated the behavioral effects of 25CN-NBOH on flexible learning in mice, a cognitive function regulated by the prefrontal cortex. An important aspect of this study was its design to isolate the long-term effects of the psychedelic by conducting testing only after two weeks had passed since the drug was administered. This helped avoid potential confounding effects from acute psychoactive impacts.
To measure flexible learning, the investigators used a novel automated reversal learning task, in which mice were trained to poke their noses into two holes in sequence to get a treat. The sequence in which to poke the holes was then reversed to track how well mice could adjust to changes in learned rules. Mice were given either a single dose of 25CN-NBOH or a saline control. After a two-week delay, both male and female mice that received the psychedelic showed significantly greater adaptability in the reversal phase of the task, as measured by poke efficiency, accuracy of trials, and number of rewards earned.
“Psychedelics such as 25CN-NBOH alter the neuroplastic structure of neurons in many parts of the brain, increasing the connectivity between key neurons,” Ahmed said. “These results show that these biological changes lead to sustained behavioral learning benefits that are still evident many weeks after a single psychedelic dose, highlighting why clinical trial designs using only one or two doses may reveal long-lasting benefits in terms of flexible learning. This is important because the fewer the doses one has to take to see long-lasting benefits, the lower the risks for potential side effects.”
Dosing psychedelics
The WashU and UM studies show the long-lasting effects of both a higher dose and a lower dose in producing brain plasticity that lasts for weeks. But might higher doses and accompanying psychoactive effects be necessary to gain maximum benefit? Current research indicates it might not be an either/or question.
Petranker noted that larger doses, while more expensive because they require therapist assistance, can be psychologically intense and provide a depth of experience, leading to a profound sense of connectedness or new personal insight that can benefit people suffering from major depressive disorder or PSTD. “Some researchers and practitioners would argue that this experience is part and parcel, perhaps necessary, for the healing process,” he said. “Once you reintroduce a sense of connection … from connectedness emerges meaning, and from meaning emerges better mental health.”
There is a need for better dosing data, Nicol added, which would include optimal dosing frequency and a better definition of the role of psychotherapy in the treatment regimen. “Right now, we don’t know what the right dose is and where do we place the psychotherapy in the context of that.”
Microdosing, where a small amount of psilocybin or other psychedelic that won’t produce a psychoactive response is used, potentially has many benefits. Some psychiatric and other health conditions, like bipolar disorder and cardiovascular conditions, may preclude a higher dose as it elevates the heart rate and blood pressure.
Looking ahead to a future with psychedelic treatments that have regulatory approval, microdoses could improve acceptance as the treatment will be less expensive and people will not feel impaired. Petranker prefers to prioritize doses that do not impair daily activities. “As long as you can do everything you normally do, you can drive, you can take care of kids, you can work, then that is an okay dose.”
Gaining regulatory approval
Hopes ran high in 2024 as clinic-stage psychedelic therapy company Lykos seemed poised to be the first company to gain regulatory approval for its MDMA-assisted therapy for PTSD. But news from the FDA was not good as the agency declined approval and requested an additional trial to support the therapy’s safety and efficacy.
Although the FDA had issues with the trial design, which included the psychotherapy portion, some in the industry hoped the treatment would gain approval, but with restrictions on how it would be administered and requirements for the company to conduct a post-approval study.
Lykos contended that many of the FDA’s requests could have been addressed with existing data or through reference to the scientific literature. The company continues to maintain close contact with the agency to work toward approval. Lykos declined an interview while it works through these issues.
Currently, two other psychedelic drugs are in Phase III trials: CYB003 from Cybin, a deuterated analog of psilocybin for the treatment of major depressive disorder; and COMP360 from COMPASS Pathways, a synthetic formulation of psilocybin for treatment-resistant depression.
The Lykos setback has not dampened enthusiasm in the field. If anything, it can provide valuable lessons to other companies pursuing regulatory approval for treatments that include both a psychedelic agent and therapy assistance.
Petranker sees the psychotherapy component of some clinical trials as a sticking point with the FDA, as evaluating and regulating therapy is outside the normal bounds of how the agency operates.
“If these substances require psychotherapeutic support, then either the mandate of the FDA and other similar regulatory agencies needs to be amended, or these drugs will not pass the threshold,” he said.
Further, the industry standard double-blind trial structure designed to keep people in a trial unaware if they are receiving the drug or a placebo is a challenge as many receiving the drug will feel its psychoactive effects. Nicol laid out ways to get around this hurdle.
“One way is to not have a full placebo arm, but to have your comparison arm be a very low dose of the same agent or of another drug, where you know that people can tell that they’re taking it,” Nicol said. Two agents that fit the bill are niacin, which elicits warmth and flushing, and benzodiazepines, which have noticeable effects on the central nervous system. Nicol also noted that trial participants will likely have tried many other drugs that did not work before enrolling in a psychedelic drug trial, so a model that has different dosing levels for the two cohorts could attract more trial participants.
“Why would a person who is really, really depressed and desperate for relief enroll in a trial if they could potentially get a sugar pill?” she asked. Further, a trial with such a design could help establish dosing levels if the low-dose cohort exhibits the same, or very similar, benefits compared with the higher dose group.
Nicol noted that continuing research and clinical validation is needed as self-dosing with these substances is increasing, even without the necessary scientific proof of safety and efficacy. “We do need the rigorous research and [to] get federal drug approvals,” she said. “But meanwhile, decriminalization is already happening, so can those two processes happen in a complimentary way?”
She also sees how the approval of these drugs could represent a sea change in mental health management. “When these become legitimate medical therapies, then the medical system will have to figure out how it’s going to accommodate delivering this care,” Nicol concluded. “It will require us to rethink our clinical care delivery in mental health.”
Chris Anderson, a Maine native, has been a B2B editor for more than 25 years. He was the founding editor of Security Systems News and Drug Discovery News, and led the print launch and expanded coverage as editor in chief of Clinical OMICs, now named Inside Precision Medicine.
