Psychedelics also target dopamine and adrenergic receptors, not just serotonin

Classical psychedelics act on a surprisingly broad range of brain receptors, not just the serotonin receptor long associated with their hallucinogenic effects, according to new research published in the journal Neuron. The study, which systematically profiled 41 psychedelic compounds, suggests that these drugs activate multiple serotonin, dopamine, and adrenergic receptors, potentially explaining both their therapeutic effects and side effects.

For decades, researchers have known that the hallucinogenic effects of compounds like LSD, psilocybin, and mescaline arise mainly from their interaction with a specific serotonin receptor in the brain known as the 5-HT2A receptor. This receptor is widely expressed in areas of the cortex involved in perception, cognition, and self-awareness, and it plays a key role in shaping how the brain interprets sensory information.

When psychedelics bind to this receptor, they trigger a cascade of neural activity that can produce visual distortions, shifts in emotional tone, a blurring of boundaries between self and environment, and altered time perception—all hallmarks of the psychedelic experience.

But while the link between psychedelics and the 5-HT2A receptor has been firmly established, that connection alone does not fully explain the wide range of effects these compounds can produce—or their potential therapeutic benefits. Recent clinical studies suggest that psychedelics may help alleviate depression, anxiety, addiction, and other psychiatric conditions, yet it remains unclear which specific molecular interactions are responsible for these outcomes. Each psychedelic compound has a distinct chemical structure, and it is likely that they interact with many different receptors beyond just 5-HT2A.

“Classical psychedelics such as LSD, psilocybin, DMT, and mescaline have long been used for medicinal and cultural purposes. In recent years, they have gained significant attention for their therapeutic potential in treating several neuropsychiatric conditions such as depression, anxiety, cluster headache, and pain,” said study author Manish Jain, a research associate at the University of North Carolina at Chapel Hill.

“Due to the burgeoning interest, there has been an unmet need for a comprehensive dataset for these compounds. Until now, available pharmacological data on psychedelics has been fragmented, generated from different assays across multiple laboratories, often with varying protocols. This patchwork has made true head-to-head comparisons between compounds difficult. Our study addresses this gap by providing the first systematic and comprehensive pharmacological profiling of psychedelics, delivering a unified dataset that will serve as a critical resource for future research and therapeutic development.”

To begin their investigation, the research team compiled a broad and chemically diverse library of psychedelic compounds. They started with a set of 255 psychoactive molecules that had previously been reported to produce psychedelic-like experiences in humans. These were identified through public databases and resources commonly used in psychopharmacology research, including Erowid, Wikipedia, and IsomerDesign.

The compounds fell into three major chemical families that include most classical psychedelics: tryptamines, phenethylamines, and lysergamides. Tryptamines include substances like psilocybin and DMT, which are structurally similar to serotonin and often found in natural sources such as “magic” mushrooms or ayahuasca. Phenethylamines include compounds like mescaline and 2C-B, which are chemically closer to dopamine and often have more stimulant-like properties. Lysergamides, such as LSD and its analogs, contain a tryptamine-derived ergoline (tetracyclic) core and tend to be highly potent and long-lasting.

To ensure they captured this diversity in their final analysis, the team used computational methods to compare the chemical structures of the 255 candidate compounds. They calculated what are known as Tanimoto coefficients—a mathematical measure of how similar two molecules are—to select a representative sample of 31 compounds that spanned the widest possible range of structures. To round out the dataset, they added 10 additional analogs from the phenethylamine and lysergamide classes due to their importance in those chemotypes, bringing the total to 41.

The team then used a computational method called the Similarity Ensemble Approach to predict how these compounds might interact with proteins in the human body. This analysis suggested that the selected psychedelics were likely to bind to a broad array of targets, not just one or two specific receptors.

To test their predictions about how these psychedelics might affect the brain, the researchers examined how each of the 41 compounds interacted with a large set of receptors. Specifically, they tested all the substances on 318 different human receptors known as G-protein-coupled receptors. These receptors are found throughout the body and brain, where they help cells communicate and respond to neurotransmitters like serotonin and dopamine. They play important roles in regulating mood, perception, attention, and other mental and physical processes.

Because LSD is known to have especially complex and long-lasting effects, the researchers also tested it on a separate group of more than 450 enzymes called kinases. These enzymes control many aspects of how cells function, and the team wanted to see if LSD might influence them in ways that could lead to side effects or unexpected actions.

The findings showed that psychedelics have a much broader impact on the brain’s receptor systems than previously thought. All 41 tested compounds strongly activated the serotonin 2A receptor, which has long been associated with psychedelic effects. But they all also acted on additional serotonin receptor subtypes, including the serotonin 2B receptor, which has been linked to heart valve disease when chronically activated.

The researchers emphasized this as a potential safety risk, especially for users who take psychedelics frequently or in microdoses over long periods. Importantly, activation of the serotonin 2B receptor occurred across all three chemical classes—tryptamines, phenethylamines, and lysergamides—suggesting that the issue is not limited to a few specific compounds.

“We found that most psychedelics strongly activate 5HT2B receptor, which has been associated with cardiac valvulopathy posing a potential safety concern,” Jain told PsyPost. “Therefore, we may need to design more precise, psychedelic-inspired molecules that avoid 5HT2B activation to mitigate cardiac valvulopathy risk.”

The study also revealed that many psychedelics engage with dopamine receptors. This was especially true for lysergamides such as LSD, which showed strong activity at dopamine D2, D3, and D4 receptors. Some tryptamines and phenethylamines also activated these receptors to a lesser extent. Dopamine receptors are associated with motivation, reward, and mood regulation, and their involvement may contribute to the stimulating and emotionally intense aspects of the psychedelic experience. The researchers confirmed these interactions using multiple functional assays and radioligand binding studies.

Adrenergic receptors, which respond to stress hormones like norepinephrine, were also activated by many of the tested compounds. These effects were again strongest among lysergamides, although some tryptamines and phenethylamines showed adrenergic activity as well. Because adrenergic receptors are involved in alertness, blood pressure regulation, and arousal, their activation may help explain the physical sensations and heightened awareness reported by many users of psychedelics.

To further understand the biological consequences of receptor activation, the researchers examined how each psychedelic compound influenced intracellular signaling pathways. They focused particularly on three types of responses: G protein activation, calcium signaling, and beta-arrestin recruitment.

Most psychedelics showed a strong bias toward activating the G alpha q signaling pathway through the serotonin 2A receptor. This pathway is associated with increases in intracellular calcium and has been linked in previous research to hallucination-like effects in animals. The team also measured beta-arrestin recruitment, which can modulate receptor sensitivity and duration of action. While most compounds activated both types of pathways to some degree, the degree of activation varied widely between molecules.

The researchers also compared the activity profiles of known hallucinogenic drugs to those of structurally similar compounds that do not produce hallucinations. One such example was lisuride, which binds to the same serotonin receptors as LSD but does not cause perceptual distortions. The researchers found that lisuride was more selective in the receptors it activated and triggered fewer downstream signaling pathways. It also showed a different pattern of signaling bias, favoring G protein activity over beta-arrestin recruitment. These differences may help explain why lisuride lacks the mind-altering properties of its hallucinogenic relatives.

“Another key finding is that, compared to non-hallucinogenic compounds, psychedelics generally engage a broader range of receptor-signaling pathways suggesting that their therapeutic likely arise from the simultaneous activation of multiple receptor-pathways networks,” Jain explained. “Importantly, this also indicates that it may be difficult to completely segregate their therapeutic potential from their hallucinogenic properties.”

The researchers also explored whether psychedelics directly interact with TrkB, a receptor involved in brain plasticity that is thought to contribute to antidepressant effects. Although some previous studies had proposed that LSD and psilocin bind directly to TrkB, this study found no evidence for such interactions. In both kinase binding assays and live-cell reporter experiments, neither compound produced significant activation of TrkB. This suggests that the plasticity-promoting effects of psychedelics likely arise from indirect signaling mechanisms, rather than direct activation of neurotrophic receptors.

To visualize how psychedelics interact with their targets at the atomic level, the researchers used cryo-electron microscopy to determine the three-dimensional structure of LSD bound to the dopamine D2 receptor. This structural data revealed specific hydrogen bonding and hydrophobic interactions that explain LSD’s high affinity for this receptor. The diethylamide portion of LSD, in particular, appeared to stabilize the molecule in a binding configuration similar to that seen in serotonin receptor complexes. The researchers also used molecular dynamics simulations to confirm the stability of this configuration and to explore how different conformations of the molecule may influence receptor activation.

Finally, the researchers compared receptor activation data with behavioral data from animal studies and dose estimates from human reports. Compounds that more strongly activated the serotonin 2A receptor—especially through the G alpha q pathway—tended to produce stronger head-twitch responses in mice, a common proxy for hallucinogenic activity. These same compounds also tended to be effective at lower recreational doses in humans. These correlations suggest that laboratory measurements of receptor activation can serve as useful predictors of psychedelic potency and subjective effect.

“We developed a comprehensive dataset for a large number of psychedelic compounds,” Jain said. “These compounds primarily act via activation of 5HT2A serotonin receptor in the brain, but they also activate several other serotonin, dopamine and adrenergic receptors. While most recent studies are mainly focused on a just few compounds such as LSD, psilocin, DMT – our resource highlights many additional analogs that may hold promise for clinical development.”

“Importantly, our findings indicate that different psychedelics can engage distinct signaling pathways, which may contribute to their therapeutic effects. As the research on psychedelic medicines continues to advance, this dataset provides a foundational resource for the scientific community and will help guide the development of safe and effective treatments.”

While the study provides a broad and detailed pharmacological profile of psychedelics, the authors caution that their experiments were conducted in non-neuronal cell lines and may not fully reflect the complexities of living brain tissue. Receptor expression, signaling dynamics, and cellular context can all influence how a compound behaves in vivo. Even so, the dataset offers a valuable starting point for researchers aiming to develop psychedelic-inspired therapeutics that minimize risks while maximizing clinical benefits.

“This study represents just the beginning of exploring psychedelic molecules,” Jain explained. “Our dataset indicates the polypharmacology of psychedelics involves the simultaneous activation of multiple signaling pathways. looking ahead, there are several exciting avenues to pursue, including mapping the complete signaling network of these compounds, crosstalk between the receptors, molecular basis of hallucinogenicity, and clarifying how these molecules exert their therapeutic effects.”

“In summary, we presented a detailed analysis of a large number of psychedelic molecules spanning three major classes: tryptamine, phenethylamine and lysergamides – at the level of receptor-G protein interactions. Our dataset reveals diverse signaling outcomes across dozens of receptors, many of which are linked to their therapeutic effects. This Neuroresource provides a foundational information to the scientific community that will support advancing the knowledge about psychedelics research.”

The study, “The polypharmacology of psychedelics reveals multiple targets for potential therapeutics,” was authored by Manish K. Jain, Ryan H. Gumpper, Samuel T. Slocum, Gavin P. Schmitz, Jakob S. Madsen, Tia A. Tummino, Carl-Mikael Suomivuori, Xi-Ping Huang, Laura Shub, Jeffrey F. DiBerto, Kuglae Kim, Chelsea DeLeon, Brain E. Krumm, Jonathan F. Fay, Michael Keiser, Alexander S. Hauser, Ron O. Dror, Brian Shoichet, David E. Gloriam, David E. Nichols, and Bryan L. Roth.