Researchers discover preventative immune benefits of a little-known psychedelic compound

A small study in mice suggests that administering a psychedelic compound before an immune system challenge can prevent brain inflammation and associated behavioral changes. The findings, published in the journal BMC Neuroscience, hint that these drugs might prime the nervous system to resist future damage.

Neuroinflammation is a biological response where the body’s immune system activates within the brain or spinal cord. While short-term inflammation helps eliminate infections, long-term or excessive immune activity can damage brain tissue. The brain is usually protected from the body’s general immune responses by a specialized cellular boundary. When severe physical stress or infection occurs, signaling molecules can breach this boundary, causing specialized brain cells to initiate a localized immune response.

When the immune system activates, cells release signaling proteins called cytokines. Some cytokines promote inflammation to attack pathogens, while others suppress inflammation to help the body heal. An imbalance leaning toward pro-inflammatory cytokines can disrupt brain circuits and alter an animal’s mood or behavior. This excessive response is a common biological feature in many brain conditions, from Alzheimer’s disease to severe depression.

Psychedelic drugs have gained attention for their ability to treat certain psychiatric conditions, but researchers are also investigating their physical effects on the brain. Many classical psychedelics bind to a specific protein on the surface of brain cells called the serotonin 5-HT2A receptor. Activating this receptor alters perception, but it also appears to influence how immune cells respond to stress. Researchers Michael Fiorillo and Javier González-Maeso of the Virginia Commonwealth University School of Medicine wanted to see if these immune-altering effects could work preventatively.

The researchers began by mapping how the mouse immune system reacts to a specific chemical trigger. They injected a small group of mice with lipopolysaccharide, a molecule found on the outer shell of bacteria. This molecule reliably provokes a strong immune reaction without causing an actual bacterial infection. Following the injection, the team measured chemical markers in the hippocampus, a brain region involved in memory and emotion.

They found that levels of pro-inflammatory cytokines peaked four hours after the injection. Specifically, the proteins interleukin-6 and tumor necrosis factor alpha reached their highest concentrations at this time. This four-hour mark became the target window for evaluating the effects of the psychedelic drug.

In a separate test, the team gave healthy mice varying doses of a psychedelic compound known as DOI. This laboratory chemical activates the same serotonin receptors as drugs like LSD and psilocybin. When they measured brain tissue 24 hours later, they found that DOI alone did not change baseline cytokine levels. The drug did not cause an immune reaction on its own.

Next, the researchers designed an experiment to test DOI as a preventative measure. They injected wild-type mice with either a low or high dose of the psychedelic compound. After waiting 24 hours, they administered the bacterial molecule to trigger systemic inflammation. Four hours after that, they measured cytokine levels in the hippocampus.

Mice that received the low dose of DOI before the immune challenge showed lower levels of interleukin-6 and tumor necrosis factor alpha. Their immune response was notably muted compared to mice that did not receive the psychedelic. The higher dose of the drug did not effectively reduce the inflammatory response, a phenomenon that sometimes occurs when cellular receptors become overwhelmed and shut down.

The team then wanted to know if this protective effect relied entirely on the serotonin 5-HT2A receptor. They repeated the prevention experiment using genetically modified mice that were bred without this specific receptor. In these modified animals, the low dose of DOI failed to prevent the spike in interleukin-6. This outcome indicates that the drug requires the 5-HT2A receptor to suppress this specific inflammatory protein.

However, the drug still successfully reduced levels of tumor necrosis factor alpha in the genetically modified mice. This suggests the psychedelic also interacts with other physiological pathways or different serotonin receptors to manage separate parts of the immune response. The researchers also observed that the modified mice experienced a much stronger overall inflammatory response to the bacterial molecule than unmodified mice. Natural serotonin activity at this receptor normally acts as a biological brake to keep the immune system from overreacting.

To see if the chemical changes in the brain translated to physical actions, the team ran a series of behavioral tests. They placed the mice in an open enclosure monitored by infrared beams to measure general movement and exploration. The bacterial molecule normally causes mice to move less, mimicking the physical lethargy people feel when they are sick.

Pretreating the mice with the low dose of DOI prevented this lethargy. The pretreated animals maintained normal movement levels despite the immune challenge. The team also evaluated the mice using a swimming test that measures passive coping, a behavior often compared to human depression. Mice that received the bacterial molecule spent more time floating passively instead of actively swimming.

Animals given the low dose of DOI beforehand remained active and spent less time floating. The researchers also tracked the animals’ body weight over a single week. The immune challenge typically causes severe weight loss, but the psychedelic treatment lessened this physical toll. The pretreated mice recovered their normal weight faster than the untreated control group.

Finally, the researchers looked for links between the chemical markers in the brain and the animals’ physical behavior. They found that higher levels of the inflammatory cytokine interleukin-6 matched up with increased passive behavior in the swimming test. Conversely, higher levels of two other cytokines associated with cellular healing aligned with more active swimming. This chemical shift points toward a more resilient biological state.

While these results offer a look at how psychedelics might shield the brain, the research relied on a single strong immune trigger. This acute response does not fully capture the persistent, low-grade inflammation seen in human neurodegenerative and psychiatric diseases. Additionally, the study evaluated whole sections of the hippocampus rather than looking at individual cell types. It remains unknown exactly which immune or nervous system cells are actually suppressing the inflammation.

The bacterial molecule and the drug were injected into the animals’ bodies rather than directly into the brain. It is possible that the psychedelic suppressed the immune response in the bloodstream first, which then reduced the secondary inflammation in the brain. The genetically modified mice used in the study lacked the serotonin receptor for their entire lives, which might have caused developmental changes that independently altered their baseline immune system.

All the experiments were conducted using male mice. Future research will need to include female animals to determine if these preventative immune effects apply equally across sexes. Scientists also need to test other psychedelic compounds to see if they offer similar protective benefits.

The study, “Pretreatment with the psychedelic DOI mitigates LPS-induced hippocampal inflammation and behavioral impairments in mice,” was authored by Michael Fiorillo and Javier González-Maeso.