β-arrestine and psychedelics such as LSD and psilocybin

When looking at psilocybin (psilocin) and LSD, it is not only interesting that they activate certain receptors, but especially how they do so and which internal signalling pathways are opened or avoided as a result. A receptor is not an on/off switch; it is rather a switching point that initiates a whole stream of biological processes. What is unique about psychedelics is that they press these switches in a way that is deeply therapeutic, while other pathways, which would produce less beneficial effects, are largely avoided. By looking at these signalling pathways one by one, it becomes much clearer why psychedelics like psilocybin and LSD have such a powerful yet gentle impact on our brain and psychological functioning.

The Gq/11 pathway: the gateway to emotional access, plasticity and awareness

The main pathway that activates both psilocybin metabolite psilocin and LSD is the Gq/11 pathway. This pathway increases calcium in the cell, activates enzymes such as PKC and triggers gene expression required for plasticity. You can think of this pathway as the foundation on which the therapeutic process rests: the brain becomes more flexible, new connections are stimulated and emotional patterns that are normally stuck suddenly come into motion. At the level of experience, this makes the inner landscape more accessible, insights arise that are normally hidden behind mental defence mechanisms, and people feel an unprecedented ability to reflect without judging themselves. The Gq/11 pathway is also implicated in increased sensitivity to music, symbolism and meaning during a session, as brain circuits that normally function rigidly are temporarily given more space to combine information in new ways.

The Gi/o route: the brake that psychedelics gently touch but mostly avoid

Whereas psilocin and LSD open the Gq/11 pathway, they remain remarkably cautious of the Gi/o pathway, a signalling mechanism involved in stress regulation, inhibition of cell activity and modulation of hormonal systems, among other things. Serotonin itself activates this pathway much more strongly, as do some antidepressants and 5-HT2C agonists such as lorcaserin. Psychedelics only do this minimally, which is beneficial because strong Gi/o activation during a therapeutic session is more likely to produce tension, physical restlessness or a sense of internal blockage. By activating this pathway only slightly, psilocybin and LSD keep consciousness clear and open, allowing emotional processes not to be compressed but rather to have space to be worked through. At the cellular level, this selectivity prevents neuronal inhibition systems from acting too quickly, allowing plasticity to be established longer and more effectively.

The G12/13 route: a path that psychedelics largely shut down and that's just as well

The G12/13 signalling pathway has little to do with the psychedelic experience, but much to do with cell growth processes, structural changes in cytoskeleton and sometimes even unwanted proliferation. This is the pathway that may have contributed to doubts surrounding the former anti-obesity drug lorcaserin. What makes this research so interesting is that psilocin and LSD almost completely avoid this route. So they deliberately steer the receptor not towards growth stimuli, but mainly towards plasticity, awareness and emotional processing. In practice, this means that these psychedelics stay on the safe side of the 5-HT2C spectrum and do not activate the cellular pathways associated with long-term effects or unwanted growth processes.

The Gz pathway: subtle, stable and different between tryptamines and phenethylamines

The Gz pathway is a somewhat special branch of the Gi/o family and is activated to varying degrees by different psychedelics. Tryptamines such as psilocin do this quite modestly, while some phenethylamines such as 2C-B can do this somewhat more strongly. The Gz pathway is involved in slow signalling processes, slight modulation of dopamine release and subtle changes in mood and motivation. In perception, this pathway mainly contributes to the “fluid” quality of the experience; a sense that thoughts become less syrupy and emotions can shift more easily. It is not a dominant route, but its gentle support sometimes makes the experience warmer or more personal, depending on the substance.

The β-arrestin pathway: desensitisation, tolerance and why psychedelics almost don't do it

β-arrestin is the molecule that pulls in a receptor when it becomes too active, causing tolerance and reduced sensitivity. Drugs that strongly activate this pathway, such as some opioids or heavy serotonin agonists, can therefore quickly produce a flat or exhausted feeling. Psychedelics hardly activate β-arrestin. This keeps the receptor active during a session, keeps the plasticity-promoting effects intact and does not cause the rapid flattening you sometimes see with other substances. In perception, this means that the experience remains organic and even without the feeling that the effect is 'falling away' or that the magic suddenly pulls out. Biologically, this limited β-arrestin activation helps to keep the therapeutic window wide and possibly also to build up less tolerance between sessions.

How all this comes together in the therapeutic experience

When all these signalling pathways are considered together, a clear picture emerges of why psilocybin and LSD are such exceptional therapeutic candidates. They open the pathways that make the brain flexible, create an open and accessible consciousness while avoiding the pathways that can cause stress, tolerance or unwanted cellular activity. This creates a state of deep emotional clarity where, with guidance, a person can let go of old patterns and form new connections, both psychological and neurobiological. As a result, the experience often feels intense but safe, deep but clear, and challenging but supportive; exactly the combination needed for true healing.