Toad psychedelic points to biological target for antidepressants

This is a summary of: Warren, A. L. et al. Structural pharmacology and therapeutic potential of 5-methoxytryptamines. Nature https://doi.org/10.1038/s41586-024-07403-2 (2024).

The problem

Psychedelics are psychoactive substances that have been used in shamanic rituals for millennia¹, but are now attracting attention because of their potential in treating neuropsychiatric disorders, including depression and substance-use disorders. Psychedelics such as psilocybin² (found in ‘magic mushrooms’), lysergic acid diethylamide (LSD) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT, found in the secretions of Colorado River toads, Incilius alvarius), have already entered clinical trials with promising early results. Yet it is still not fully understood how these drugs engage molecular targets in the brain, and how this leads to their therapeutic and hallucinogenic effects. Many psychedelics (including 5-MeO-DMT) are chemically similar to the neurotransmitter serotonin, and bind to several of the 12 human G-protein-coupled serotonin receptors³. Most studies have focused on the 5-HT_2A serotonin receptor, but little is known about the role of other serotonin receptors, which might have a crucial role in the complex psychoactive and therapeutic effects of these drugs.

The discovery

Using a highly interdisciplinary approach, we set out to investigate how the most prominent psychedelics — LSD, psilocybin, mescaline (peyote), N,N-dimethyltryptamine (DMT, found in the psychedelic brew ayahuasca) and 5-MeO-DMT — trigger biological signalling through receptors other than 5-HT_2A. We found that 5-MeO-DMT is almost equally active at 5-HT_2A and 5-HT_1A, a serotonin receptor that has previously been implicated⁴ in the behavioural effects of 5-MeO-DMT. To understand the effects of the 5-HT_1A activity of 5-MeO-DMT we implemented a medicinal chemistry programme, guided by the cryo-electron microscopy structures of psychedelics bound to 5-HT_1A, to discover 5-MeO-DMT-like compounds that selectively act through 5-HT_1A, and not through 5-HT_2A. We then used the most 5-HT_1A-selective compound in behavioural studies in mice to investigate the role of 5-HT_1A in the hallucinogenic and antidepressant effects of 5-MeO-DMT.

We first discovered that 5-MeO-DMT and serotonin bind to 5-HT_1A in different ways — a finding that enabled the rational design of a series of 5-HT_1A-selective compounds based on the structures of the receptor in complex with 5-MeO-DMT or serotonin. The most selective compound in this series binds to 5-HT_1A in a similar way to clinically used antidepressants and anti-anxiety agents such as buspirone. Indeed, we found that a 5-HT_1A-selective 5-MeO-DMT analogue produced no signs of hallucinations in animal models, but still showed potent antidepressant effects (Fig. 1). These findings suggest that receptors other than 5-HT_2A not only modulate behavioural effects caused by psychedelics, but possibly also contribute substantially to their therapeutic potential.

The implications

Psychedelics cause a wide range of subjective effects in users, which vary even more greatly between different drugs⁵. Our studies further emphasize how serotonin receptors such as 5-HT_1A probably modulate the subjective effects of the psychedelic experience, in addition to having a potentially pivotal role in their therapeutic effects. Given the heterogeneity and complexity of depression and psychiatric conditions in general, our studies strengthen the case that specific psychedelics will be most suitable for treating distinct types of depression.

Despite our finding that a 5-MeO-DMT derivative lacks hallucinogenic-like effects while retaining antidepressant-like activity in mice, it remains to be seen whether these results translate to humans. Furthermore, our studies focused solely on the role of 5-HT_1A in the pharmacology of 5-MeO-DMT, but serotonin receptors other than 5-HT_1A and 5-HT_2A probably also contribute to the subjective and therapeutic effects of many psychedelics.

We are currently pursuing multiple lines of further research. For instance, we are investigating which brain circuitry is responsible for 5-HT_1A-mediated modulation of psychedelic effects, and how the psychoactive profile of analogues of 5-MeO-DMT changes as their selectivity for 5-HT_1A versus 5-HT_2A increases. We are also looking into the role of other serotonin receptors in the molecular and behavioural pharmacology of psychedelics. — Daniel Wacker is at the Icahn School of Medicine at Mount Sinai, New York City, New York, USA, and Dalibor Sames is at Columbia University, New York City, New York, USA.

Behind the paper

D.S. and I had long known about each other’s work, but had never met. I was therefore excited when he reached out about a possible collaboration in 2020. We quickly discovered our shared opinion that there had been too much focus on 5-HT_2A in psychedelics research, and that other receptors were under-investigated. That was the start of our joint study, even though neither of our laboratories has been able to secure funding for psychedelic work. However, D.S. and I had funding to study iboga alkaloids, which are structurally related to 5-MeO-DMT and serotonergic signalling. Perhaps the most difficult part of this work was the iterative synthesis and characterization of more than 100 compounds, which took several years. But it was that much more exciting when we found that the most 5-HT_1A-selective 5-MeO-DMT analogue showed antidepressant-like effects without the 5-HT_2A-related hallucinations. — D.W.