Every month, the BCSP brings you one essential read to keep you up to date with the leading topics in psychedelic science. This month, postdoctoral researcher Sean Noah explains “Structural pharmacology and therapeutic potential of 5-methoxytryptamines,” published in 2024 in Nature.
In a new article published in Nature entitled “Structural pharmacology and therapeutic potential of 5-methoxytryptamines,” researchers describe a series of experiments that expand our understanding of how a mysterious group of psychedelics exert their powerful and strange psychoactive effects. The experiments revealed that these peculiar compounds, which include 5-MeO-DMT, bind with high affinity to two types of serotonin receptors in the brain. Furthermore, the experiments showed that different effects can be attributed to the two receptors: hallucinations to one type of receptor, and anti-anxiety and anti-depressant effects to the other.
A Distinction in the Animal Kingdom
The 5-methoxytryptamines are named for the attachment of a methoxy group — a combination of carbon, hydrogen, and oxygen — to a particular position on the tryptamine chemical skeleton that is common to many psychedelics. One of the more well-known members of this chemical family is 5-methoxy-dimethyltryptamine, also known as 5-MeO-DMT. This psychedelic is best known for being the psychoactive ingredient in the venom of the Colorado River toad, Incilius alvarius, which lives in the Sonoran Desert.
Psychedelic compounds are abundant in the natural world, produced by hundreds of species of fungi and plants. But animals that produce psychedelics are comparatively rare. The Colorado River toad is the only animal known to secrete a psychedelic compound from its body. This desert dweller produces 5-MeO-DMT from glands on its warty, greenish-gray skin. The modest appearance of this unassuming amphibian contrasts starkly with the profound experiences induced by its secretions.
Reports from users of 5-MeO-DMT often describe experiences that are intense, otherworldly, and overwhelming. However, use of 5-MeO-DMT has also been observed to cause rapid reductions in symptoms of depression and anxiety and increases in positive states like feelings of meaningfulness and spiritual significance. Based on its potential to induce positive psychological changes, 5-MeO-DMT is being studied as a therapeutic for multiple psychiatric conditions.
Chemical Reactions
In the brain, 5-MeO-DMT activates the serotonin receptor subtype known as the 5-HT1A receptor (“5-HT” is shorthand for 5-hydroxytryptamine, serotonin’s chemical name). There are at least twelve different classes of serotonin receptors in the human brain, and psychedelics are thought to interact with many of them, along with other types of neurotransmitter receptors and molecular targets. However, one particular serotonin receptor subtype, the 2A receptor, is thought to play the most important role in the hallucinogenic effects of psychedelics.
The results of numerous studies involving human volunteers and animal test subjects suggest that psychedelic experiences arise because psychedelic compounds fit hand-in-glove into 5-HT2A receptors, resulting in sustained neural signaling. LSD molecules, for example, will normally bind tightly to 5-HT receptors in the brain. But if volunteers take a 5-HT2A receptor blocker before taking LSD, they report that the LSD has no detectable psychoactive effect. Activation of 5-HT2A receptors is thus thought to be a necessary condition for the subjective psychedelic experience.
The reported effects of 5-MeO-DMT are distinct from those of classical psychedelics like LSD, psilocybin, and mescaline: often, users of 5-MeO-DMT describe rapidly increasing intensity, disorientation, and profound disconnection from their environment. This raises the question: Does the compound have a different, distinct pattern of interactions with neurotransmitter receptors?Previous studies revealed glimpses of an answer: the observable effects of 5-MeO-DMT in the behavior of rodent test subjects seemed to mostly reflect activation of not the 5-HT2A receptor, but instead its cousin, the 5-HT1A receptor. With this intriguing clue as a starting point, the new study published in Nature has further revealed how 5-MeO-DMT interacts with 5-HT1A and 5-HT2A receptors and how these receptors might differentially contribute to the drug’s complex effects.
A Series of Experiments
The researchers performed multiple experiments to better understand how the 5-methoxytryptamine family interacts with 5-HT1A and 5-HT2A receptors. First, using cryo-electron microscopy, they observed how 5-MeO-DMT falls into place in the physical structure of the 5-HT1A receptors. They determined that the 5-MeO-DMT molecule sits deeper down in the 5-HT1A receptor than serotonin itself does, suggesting a possible explanation for its particular binding affinity for the 5-HT1A receptor.
Next, the researchers sought to explore the specific aspects of the chemical structures of the 5-methoxytryptamines that endow them with high binding affinity for 5-HT1A and 5-HT2A receptors. To do so, the researchers systematically modified 5-MeO-DMT’s amine and indole components, which are two of the important elements of the chemical structure of this family of psychedelics. The researchers then measured the effects of these modifications on binding affinity for 5-HT1A and 5-HT2A receptors.
The researchers then combined the results of their modification experiments with their computational model of 5-MeO-DMT sitting in the 5-HT1A receptor that they created based on their electron microscopy results. They were able to identify one particular amino acid, A365, in the protein sequence of the 5-HT1A receptor that sat close to a site on the bound 5-MeO-DMT derivatives that plays an important role in whether a given derivative compound had high binding affinity for the 5-HT1A receptor. They then created 5-HT1A receptor variants with a different amino acid at this critical location. Amazingly, they found reduced binding affinity among their test compounds for the altered 5-HT1A receptors.
The researchers then sought to disentangle the individual roles that 5-HT1A and 5-HT2A receptors play in the complex effects of 5-MeO-DMT and related psychedelics. Based on their earlier results from modifying components of the chemical structure of 5-methoxytryptamines and then measuring binding affinity for 5-HT1A and 5-HT2A receptors, they selected a derivative compound (called 4-F,5-MeO-PyrT) that is more than 800-fold selective for 5-HT1A over 5-HT2A receptors. Their test compound has practically no binding to 5-HT2A receptors, so it could be used to study the individual effects of 5-HT1A receptor activation.
The researchers administered their test compound to mice and observed a dose-dependent effect on locomotor activity suppression, a behavioral measure of 5-HT1A receptor activation that had been identified in previous studies. On the other hand, there was no dose-dependent effect on the head-twitch response of the mice — a behavioral measure that is thought to reflect activation of 5-HT2A receptors and resulting subjective perceptual effects. Together, these findings suggest that the test compound was indeed affecting signaling through the 5-HT1A receptor while not having any effect at the 5-HT2A receptor. The critical question that the researchers wanted to answer was whether their 5-HT1A receptor-selective test compound would have anti-anxiety and antidepressant effects. If so, then the 5-HT1A receptor would be a candidate for mediating the therapeutic effects of this class of psychedelics in humans. Using a mouse model of depression and social avoidance, the researchers showed that indeed, their 5-HT1A receptor-preferential test compound alleviated depression and anxiety behaviors.
Infinite Receptor Diversity in Infinite Combinations
This new research shows that 5-HT1A receptors play an important role in positive psychological change that can be brought on by 5-MeO-DMT. But this work also underscores how significant aspects of psychedelic experiences may be due to receptors that we currently know very little about. Psychedelics interact with many different types of receptors, transporters, and other molecular targets, and different psychedelic compounds interact with these targets in varying degrees and with varying effects. Scientists are just starting to uncover this complex interplay, and there is a vast amount of work still to accomplish. Thankfully, as this new article demonstrates, with careful experimentation and sophisticated methods, the research community is up to the task.
Want to read more? Dive into the full article. You can also find it in the BCSP Resource Database.