How Psychedelics Make Someone “Trip”

When a person takes a classic hallucinogenic psychedelic such as psilocybin, LSD, or DMT, the experience of tripping arises from a very specific cascade of receptor-level and network-level events in the brain. It all begins at the 5-HT2A receptor, a serotonin receptor subtype found in high density in the prefrontal cortex, posterior cingulate cortex, and layer V pyramidal neurons of the cortex.

1. 5-HT2A Activation and Signal Bias

Hallucinogenic psychedelics are potent 5-HT2A agonists, but what makes them special is how they activate the receptor. They do not merely switch it “on” like serotonin does. Instead, they bias the receptor toward dual signaling through both

• the Gq protein pathway, which releases intracellular calcium ions (Ca²⁺) and activates phospholipase C, and
• the β-arrestin pathway, which alters receptor trafficking, gene expression, and neural plasticity.

This mixed Gq + β-arrestin signaling is far stronger and more sustained than the transient signal produced by serotonin itself. That prolonged intracellular activity triggers waves of excitation across cortical neurons.

2. Sustained Calcium Signaling and Cortical Excitability

Through the Gq pathway, psychedelics generate sustained calcium spikes inside layer V pyramidal neurons — the cells responsible for integrating sensory input and sending long-range signals throughout the brain. This increases neuronal firing variability and promotes cross-talk between normally segregated brain networks.

3. Cortical Desynchronization and Network “Rewiring”

Under normal conditions, brain networks such as the default mode network (DMN), salience network, and executive control network operate in rhythmic coordination. Psychedelics disrupt this synchronization, producing cortical desynchronization — the neural equivalent of breaking the usual “filters” that maintain a coherent sense of self and reality.

This desynchronization allows higher-order sensory and associative regions to communicate more freely with each other and with lower sensory cortices. Functionally, it manifests as

• synesthesia (blending of senses),
• altered time perception,
• hyper-connected imagery, and
• ultimately ego dissolution, when the DMN — the neural correlate of the self — loses its dominant, organizing influence.

4. Long Residence Time and Prolonged Effect

Many hallucinogens (notably LSD) have exceptionally long receptor residence times — they remain bound to 5-HT2A receptors for hours, continuing to drive signaling long after serotonin would have detached. This persistence sustains the altered network dynamics that produce the extended duration of a trip.

5. Contrast with Non-Hallucinogenic Psychoplastogens

Compounds designed to avoid the trip, such as tabernanthalog (TBG) or AAZ-A-154, interact with the same receptor but do so differently. They show weak partial activation of Gq and almost no β-arrestin recruitment, leading to short, transient calcium transients and preserved network stability. They still induce plasticity — dendritic growth and BDNF upregulation — but without the perceptual disintegration and ego loss that come from the prolonged cortical chaos.

In Summary

You “trip” not simply because a drug activates 5-HT2A receptors, but because it activates them in a prolonged, unbalanced, and multidimensional way, sending cortical neurons into a sustained state of hyper-connectivity and desynchronization. The collapse of hierarchical control within brain networks — particularly the default mode network — gives rise to vivid perceptual distortions, expanded consciousness, and the temporary loss of the ordinary sense of self.