Psilocybin shows promise in OCD treatment — even without the psychedelic “trip”

Blocking the subjective psychedelic effects of psilocybin does not appear to interfere with the substance’s ability to potentially help with obsessive behaviors, according to new research published in Translational Psychiatry. The findings contribute to the growing body of research on the clinical application of psychedelics in psychiatry and highlight the need for further investigation in clinical trials to evaluate the efficacy and safety of psilocybin in the treatment of obsessive-compulsive disorder (OCD).

Psilocybin is a naturally occurring psychedelic compound found in certain species of mushrooms, often referred to as “magic mushrooms.” It is a serotonergic hallucinogen that can produce profound alterations in perception, mood, and cognition.

Psilocybin has shown promise as a potential therapeutic agent for various mental health conditions, including depression, anxiety, post-traumatic stress disorder (PTSD), and addiction. Preliminary studies have suggested that psilocybin-assisted therapy can have long-lasting positive effects on mental well-being and quality of life.

OCD is a debilitating disorder characterized by uncontrollable thoughts and repetitive behaviors. While current treatments such as antidepressants and cognitive behavioral therapy can be effective, a significant number of patients do not respond to these treatments, highlighting the need for alternative therapeutic options.

“We are very interested in the potential of psychedelic drugs to treat psychiatric disorders, particularly in patients who do not respond well to standard medications,” explained study author Bernard Lerer, a psychiatry professor at Hebrew University. “For that reason, we founded the Hadassah BrainLabs Center for Psychedelic Research where we do extensive research on psychedelic drugs. Obsessive-compulsive disorder (OCD) is one of the conditions in which a high proportion of patients do not respond well to standard treatment – at least a third.”

“There is preliminary evidence from studies in patients that psilocybin can help patients with OCD. But psilocybin induces a psychedelic trip and this requires special management. We think that psilocybin could help patients with OCD without the trip. How do we achieve this?”

“We have shown in a different study that the medication, buspirone, which is used to treat anxiety, blocks a mouse equivalent of the psychedelic trip and another researcher has shown that it does so in humans,” Lerer explained. “We wanted to find out whether psilocybin would be effective in a mouse model for anti-obsessional effects – marble burying – and whether it would do so even in the presence of buspirone, which blocks the trip.”

The study utilized a preclinical model called the marble-burying test, which measures the propensity of rodents to dig and cover objects placed in their cages. This test is considered to have reasonable predictive validity for identifying drugs that may be effective in treating OCD. Previous studies using the marble-burying test have shown that psilocybin and other psychedelic compounds reduce marble burying in mice, suggesting their potential therapeutic effect in OCD.

In this study, the researchers aimed to examine the role of serotonin 2A (5-HT2A) receptors, which are the primary target of psilocybin, in its effect on marble burying. They also sought to investigate the involvement of serotonin 1A (5-HT1A) receptors, another serotonin receptor subtype, in psilocybin’s effect. Additionally, the study explored the impact of different administration methods and the persistence of the anti-marble-burying effect after 7 days.

The researchers conducted the experiments using male mice. They administered various drugs, including psilocybin, escitalopram (an SSRI), and other compounds that selectively target 5-HT2A and 5-HT1A receptors, through intraperitoneal injection. The mice underwent the marble-burying test, where the number of marbles buried by the mice was measured after drug administration. They also performed an open field test to assess locomotor activity and a head twitch response test, which is associated with psychedelic effects.

The results of the study showed that mice treated with psilocybin buried significantly fewer marbles compared to the control group. This reduction in marble burying was similar to the effect observed with escitalopram, indicating that psilocybin may have a similar therapeutic effect as antidepressant medication in the treatment of OCD.

Interestingly, blocking the 5-HT2A receptors using a selective antagonist (known as M100907) did not prevent the anti-marble-burying effect of psilocybin, suggesting that this effect is not mediated solely by 5-HT2A receptor activation. On the other hand, buspirone, a 5-HT1A receptor agonist, blocked the effects of psilocybin on the head twitch response test, but did not impeding its psilocybin’s effect on marble burying.

“Mice administered psilocybin with buspirone performed as well on the marble burying test as mice administered psilocybin without buspirone,” Lerer told PsyPost. “The results were clear even though buspirone prevented the trip. Our findings mean that we could potentially treat patients with OCD with the two drugs together and help their OCD without causing them to have a psychedelic trip. That would be very important clinically.”

The study also investigated different administration methods and found that psilocybin administered as a staggered dose had a similar effect on marble burying as a single bolus injection. Additionally, the anti-marble-burying effect of psilocybin persisted for at least 7 days, indicating a potential long-lasting therapeutic effect.

“There is an important role for psychedelic drugs to treat psychiatric disorders that are not helped by standard treatment,” Lerer said. “Worldwide millions of people are in need of alternative treatment. Our study suggests that there is a way to treat OCD with psilocybin without the patient having to undergo a full scale psychedelic trip. Planning is under way for a clinical trial to test this suggestion.”

The study provides further evidence for the potential therapeutic effect of psilocybin in OCD using a preclinical model. But some limitations should be noted. The study used mice as an animal model to assess the effects of buspirone and psilocybin on marble burying behavior. While animal models can provide valuable preliminary data, the results may not directly translate to humans.

“Like all discoveries in mice, the ultimate test is in people,” Lerer said. “However, buspirone has already been shown to reduce the psychedelic trip in humans so there is already support from human studies.”

“People interested in learning more about Psychedelic Medicine can register for Psychedelic Medicine – Israel 2023, which will be held in Tel Aviv on December 10-13, 2023 and will cover all cutting edge areas of psychedelic medicine,” Lerer added.

The study, “Effect of psilocybin on marble burying in ICR mice: role of 5-HT1A receptors and implications for the treatment of obsessive-compulsive disorder“, was authored by Sandeep Singh, Alexander Botvinnik, Orr Shahar, Gilly Wolf, Corel Yakobi, Michal Saban, Adham Salama, Amit Lotan, Bernard Lerer, and Tzuri Lifschytz.