Paper Claims Psychedelics Exert Antidepressant Effects By Binding to TrkB, Not 5-HT2A

A paper in Nature Neuroscience caused quite a stir last week. A group of researchers at University of Helsinki claim that LSD and psilocin “directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants”, binding to “distinct but partially overlapping sites within the transmembrane domain of TrkB dimers.”

TrkB is the receptor for brain-derived neurotrophic factor (BDNF), which is instrumental in the growth and survival of neurons and the promotion of neuroplasticity, among other functions.

An earlier paper from the group claimed that both fluoxetine and ketamine act by directly binding to TrkB (Casarotto et al., 2021), too.

The group’s thesis appears to fly in the face of a prominent tenet in some corners of psychedelic research that maintains it’s the 5-HT2A receptor primarily mediating the apparent therapeutic effects of psychedelics. “To date, most papers focusing on psychedelics’ neurotrophic actions never provided a convincing alternative path to 5-HT2A of this magnitude”, psychedelic researcher and drug developer Mario de la Fuente told Psychedelic Alpha.

Speculating on why this paper has sparked so much discussion within the psychedelics research community, de la Fuente said that the researchers, “didn’t fill in the gap with a mechanistic speculation, they provided biophysical evidence of a direct interaction between LSD, psilocin, lisuride and the BDNF receptor TrkB… and they did so with a compendium of methodologies.”

What’s more, the group claims that the effects of LSD and psilocin on “neurotrophic signaling, plasticity and antidepressant-like behavior in mice” are not only dependent on TrkB binding and the associated promotion of endogenous BDNF signalling, but that these effects are independent of 5-HT2A activation. This was ascertained by employing 5-HT2A antagonists. LSD-induced head twitching, meanwhile, is independent of TrkB binding but dependent on 5-HT2A activation.

Put simply, the group is implying that TrkB is responsible for the therapeutic effects of the psychedelics under study, while 5-HT2A is responsible for the psychedelic effects (using head-twitch in mice as a proxy).

The upshot is that the group believes there may be potential in developing non-hallucinogenic psychedelic-inspired antidepressants that work by binding to TrkB but lack 5-HT2A activity. In this sense, they might resemble something akin to ‘better’ or ‘stronger’ SSRIs. Indeed, the paper discloses that seven of the co-authors are inventors on a patent application related to the filings.

In the past decade, some groups have sought to develop TrkB Positive Allosteric Modulators (PAMs) for neurodegenerative disorders, though research remains sparse.

Elsewhere, Semax—a drug that’s almost exclusively used in Ukraine and its occupier, Russia—rapidly increases levels of BDNF and expression of TrkB in the hippocampus of animals studied. It’s used to aid recovery from stroke and transient ischemic attack as well as hypoxia and other conditions. Aside from its apparent neuroprotective properties it’s found further interest among biohacker enthusiasts for its potential cognitive enhancing effects, where it’s often categorised as a nootropic. In 2007, a psychiatrist based at the Catholic University of Korea College of Medicine, in Seoul, wrote that further research into the potential role of Semax in treating depression was warranted. There have been no published trials of Semax outside of the former Soviet sphere.

Back to the present discussion: it’s much too early to throw out other theories of psychedelics’ primary mechanism of action just yet, given that the findings are yet to be replicated and the fact that we’re looking at mouse brains at this stage. But, this paper has generated healthy discussion surrounding the uncertainty of psychedelic mechanisms of action.

Given the magnitude of the findings, it won’t be long before we see peers attempting to replicate this work, expand on the hypothesis and evaluate the specificity of Moliner et al.’s findings with other chemotypes”, de la Fuente told us.

It looks like it might not be too long before we start to hear from labs looking to replicate the findings. University of North Carolina’s Bryan Roth told Psychedelic Alpha that his lab is attempting to do just that, and as de la Fuente points out: they surely won’t be alone.