ABOVE: Lindsay Cameron, Olson lab, UC Davis

Besides inducing “trips,” psychedelics such as LSD—administered in parallel to psychological support—have been shown to have beneficial effects in cases of depression, anxiety, and addiction. Although these clinical observations tend to be weakened by the absence of adequate placebo-controlled conditions, several research groups are joining efforts to understand how these drugs can sometimes surpass common antidepressants in efficacy and speed.

An intriguing observation is that, although these effects are known to be mediated by one of 14 specific serotonin receptors (2A), that receptor’s natural ligand, the neurotransmitter serotonin, does not induce these same results. A study published in Science last week (February 16) suggests that the key to understanding why the drugs work when the neurotransmitter doesn’t may lie in the location of the receptors to which hallucinogens bind. According to the authors, the chemical structures of psychedelics allow them to cross the plasma membrane and activate intracellular receptors that are not easily accessible to serotonin itself. Other experts in the field say that the findings could help researchers develop novel, nonhallucinogenic therapeutics for depression and related conditions.

See “Psilocybin Relieves Some Treatment-Resistant Depression Cases: Trial

Previous studies had shown that psychedelics promote spinogenesis—the development of new dendrites in neurons—allowing them to connect with other cells and thus promoting neuroplasticity, which is likely behind their therapeutic effect. The serotonin 2A receptor, which is highly expressed in the brain cortex, is essential to this psychedelics-induced neural plasticity. But that “left [us] with this question [of] why can’t serotonin, a very good agonist of the serotonin 2A receptor, produce the same types of effects,” says UC Davis Institute for Psychedelics and Neurotherapeutics director David Olson. So he and his colleagues dug into potential explanations, says Olson, who led the new study and is also the cofounder, chief innovation officer, and head of the scientific advisory board of Delix Therapeutics, a company that supported part of this study.

Olson says they got their first “glimpse at a decent hypothesis” when they tweaked the chemical structures of serotonin and serotonin-like molecules to see how this “impacted their functional properties.” They found that methylation of these molecules, which makes them less polar, increased their efficacy to promote neural plasticity. To Olson, that indicated that the “greasiness” of these compounds—that is, their likelihood to diffuse across nonpolar environments, such as the interior of the plasma membrane—was somehow related to their ability to induce neuroplasticity. And, altogether, that hinted at the idea that perhaps the 2A receptors are located inside the cells, and therefore, that molecules had to cross the cell’s outer membrane in order to bind to them, he says.

The researchers tested this hypothesis with a series of experiments. By tagging the serotonin 2A receptor with fluorescent proteins, they observed a large pool of them inside cortical neurons. Then, they chemically modified DMT (found in the Amazonian psychoactive brew ayahuasca) and psilocin (present in “magic” mushrooms) to make membrane-impermeable versions. They then assessed both the original and more polar varieties’ ability to promote dendrite growth in rat embryonic cortical neurons with intact membranes or with temporary holes cut into the membrane via electroporation. It turned out that while membrane-permeable compounds succeeded in both scenarios, the impermeable ones did so only when exposed to more permissive membranes. In an equivalent, reversed experiment, serotonin itself was able to induce dendritic growth only when exposed to electroporated membranes.

A cortical neuron in gray expressing serotonin 2A receptors (dots in various colors).
A cortical neuron (gray) expressing serotonin 2A receptors (colors)
Max Vargas

Finally, the team tested whether facilitating the entry of serotonin into cortical neurons could imitate the effects of psychedelics in mice. By genetically engineering a serotonin transporter in these neurons, which resulted in an increase of the neurotransmitter inside them, the authors found that these animals had increased dendrite density and exhibited behaviors that are used as proxy for antidepressant-like effects, emulating the effects of psychedelics.

These data may explain why different ligands for that same serotonin 2A receptor do not elicit the same response. According to Olson and colleagues, the answer is that DMT and psilocin reach those located intracellularly while serotonin does not.

But these observations also raise the “intriguing” question of why there is such a high density of 2A receptors in an area where serotonin can’t access them, says Olson. “Does that mean that there’s something else that can activate them?” he wonders aloud. There could be, for instance, a psychedelic-like compound produced by the body that’s able to bind to them, the team speculates in their study. Or, “does it mean that they’re just an inactive pool waiting to get exported to the cell surface?” Olson says. These are still open questions.

Yet, it cannot be completely ruled out that serotonin is able to enter the cells, says Laura Bohn, a neuropharmacologist at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology in Jupiter, Florida. For instance, there is evidence that serotonin is involved in intracellular processes and that the neurotransmitter can cross the plasma membrane through a diffusion-like process. Bohn was not involved in the study but is on the scientific advisory board of Onsero, a preclinical neurobiology company.

In any case, these results could potentially help in the development of drugs to treat neuropsychiatric disorders, says Virginia Commonwealth University neuropharmacologist Javier González-Maeso, who did not participate in the study but provided one of the plasmids used in it. The goal would be to eventually “design drugs that do not induce hallucinations as psilocin or LSD do, but still . . . could induce these fast-acting and long lasting” effects, he explains. Based on these observations, one could think of perhaps designing more hydrophobic drugs, he adds.

“I think that the better you understand the mechanism of psychedelic-induced neuroplasticity, perhaps we will be able to design more targeted therapeutics with improved safety and efficacy profiles,” says Olson. “That’s probably . . . the most important takeaway from the study,” he says.