Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and its pharmacologically active metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine) are the major psychoactive alkaloids in several species of “magic” mushrooms. They are tryptamine/indolamine hallucinogens, and are structured similarly to serotonin. 

Psilocybin and psilocin are partial agonists, which means that they only partially activate the receptor they bind, and thus have only partial efficacy at the receptor compared to full agonists. This is important when considering combining psilocybin with prescription drugs for depression. Furthermore, drug affinities do not correlate with clinical efficacy, meaning that the serotonergic neurotransmitter displays varying binding affinities at different serotonergic receptor sites.

 
Psilocin is highly lipophilic, and thus able to cross the bloodbrain barrier and bind to several serotonergic receptors (i.e. receptors which use serotonin as their neurotransmitter). It has an especially high affinity to 5-hydroxytryptamine 2A (5-HT2A) receptor. In contrast, psilocybin is hydrophilic and cannot cross the blood-brain barrier. 

As is the case with other tryptamine psychedelics (such as LSD and DMT), psilocin’s effect on the individual is created because it can act functionally selective in relation to the 5-HT2A receptors, using the psychedelic pathway instead of the serotonin pathway. This results in an increased glutamate release. Glutamate is the most abundant excitatory neurotransmitter in our central nervous system, and essential for all of our behaviors: it regulates neurogenesis, neurite outgrowth, synaptogenesis and programmed cell death (apoptosis).

It is this increased presence of glutamate which is likely the cause of the psychedelic effect while tripping. 

To make visual sense of this, have a look at the brain without (a) and with (b) psychedelics:

Image: Communication between brain networks in people given psilocybin (right) or a non-psychedelic compound (left). PETRI ET AL./PROCEEDINGS OF THE ROYAL SOCIETY INTERFACE.

The colored circles correspond to networks in the brain which are especially rich in connections. The co-author of the study, mathematician Giovanni Petri, explains that the well-ordered correlation state in normal brains is changed by the presence of psilocybin: “Suddenly the networks are cross-linking like crazy, but not in random ways.”

The longer lasting effects, i.e. changes that are made structurally and organically in the brain are, say the experts, due to the way psilocin chooses the psychedelic instead of the serotonergic neurobiological signaling pathways. The changes in neuroplasticity are induced through (but are not limited to) an increased expression of glutamate and brain-derived neurotrophic factor (BDNF) (28, 29).

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These mechanisms of increased neuroplasticity can help patients learn new ways of coping and responding to stressors, develop and integrate new techniques of self-soothing and build resilience as key parts of their recovery.

References:

Petri, G., Expert, P., Turkheimer, F., Carhart-Harris, R., Nutt, D., Hellyer, P. J., & Vaccarino, F. (2014). Homological scaffolds of brain functional networks. Journal of the Royal Society, Interface, 11(101), 20140873.