The polypharmacology of psychedelics reveals multiple targets for potential therapeutics

Classical psychedelics such as DMT, psilocybin, and mescaline have long histories of use in spiritual and medicinal contexts, particularly among Indigenous cultures. These substances are known to elicit a variety of subjective experiences, including vivid hallucinations, emotional fluctuations, a diminished sense of self (commonly referred to as ego dissolution), and heightened feelings of interconnectedness. The specific effects depend not only on the substance and dose but also on the individual’s mental state and environment. In recent years, these compounds have attracted significant scientific attention for their potential to treat a range of neuropsychiatric conditions, including depression, anxiety, post-traumatic stress disorder (PTSD), substance use disorders, and headache disorders such as migraines and cluster headaches.

From a chemical perspective, classical psychedelics are typically classified into three main categories: tryptamines (e.g., DMT and psilocybin), phenethylamines (e.g., mescaline), and lysergamides (e.g., LSD). Tryptamines share structural similarities with serotonin, a neurotransmitter involved in mood and perception. Phenethylamines more closely resemble dopamine, a neurotransmitter associated with motivation and reward. Lysergamides contain a tryptamine core fused with a rigid tetracyclic ring structure. These substances exert their characteristic psychedelic effects primarily through activation of the serotonin 2A receptor (5-HT2AR), which is highly expressed in the brain’s cortex, especially in layer 5 pyramidal neurons.

Activation of 5-HT2AR triggers a signalling cascade that involves intracellular calcium release, neuronal firing, and recruitment of additional signalling proteins, including β-arrestins and postsynaptic density scaffolding proteins like PSD-95. However, the specific molecular mechanisms responsible for the therapeutic benefits of psychedelics remain unclear. Some studies have suggested that these effects may be linked to the promotion of dendritic spine growth—small protrusions on neurons associated with synaptic plasticity. This process may depend on 5-HT2AR activity, alternative serotonin receptors, or interactions with other proteins such as the TrkB receptor. To clarify these mechanisms, the authors aimed to profile a broad range of psychedelic compounds against hundreds of molecular targets to explore their full pharmacological activity and potential relevance to therapy and safety.

Methods

Compound Selection and Computational Predictions