Psilocybin

Psilocybin is a serotonergic classic psychedelic of natural origin, found in many mushrooms (Psilocybe spp.). It is a prodrug: inactive in itself, it is converted in the body into psilocin, which acts mainly through the 5-HT2A receptor, with participation of the 5-HT2C and 5-HT1A receptors.

Pharmacology

Psilocybin is an inactive prodrug, rapidly converted into psilocin (4-hydroxy-DMT), the actual psychoactive compound. Psilocin acts as a serotonergic partial agonist. The 5-HT2A receptor is its main psychedelic mediator, while the 5-HT1A and 5-HT2C receptors modulate the affective and cognitive tone.

Unlike LSD, psilocybin shows little or no significant dopaminergic component. A key feature for clinical use is that it is a stable molecule, given orally, compatible with clinical standardisation.

Mechanisms

At the level of brain networks, psilocybin temporarily reduces the cohesion of the default mode network (DMN) and increases global connectivity between networks that are usually separate. Hierarchical filtering decreases, in favour of greater brain entropy and increased communication between perception, emotion and cognition.

In concrete terms, one observes a decrease in DMN activity and cohesion (notably in the medial prefrontal cortex and the precuneus), an increase in global connectivity, an increase in brain entropy, and a transient reorganisation of information processing.

Phenomenology

Functionally, psilocybin produces a profound alteration of perception, consciousness and the organisation of the self. Reported effects include visual alterations (colours, forms, movements, synaesthesias), more fluid and associative thought with heightened creativity, as well as partial or strong ego dissolution and a possible sense of unity.

These are frequently accompanied by empathy and a sense of connection to living things, emotional openness, alteration of time and space, and complete-type mystical experiences, more frequent than with many other psychedelics. Typical subjective effects include rich and complex visual perceptions, organic patterns, introspection with new perspectives, and a dilated sense of time accompanied by amplified emotions and wonder. The therapeutic potential is studied in depression, end-of-life anxiety and addictions.

Psilocybin occupies a unique place among psychedelics: a stable prodrug, an intermediate duration compatible with a clinical setting, and a strong capacity to induce complete-type mystical experiences correlated with lasting effects. It differs from LSD by a texture often described as more organic, shorter, and without a marked late dopaminergic phase. It is not merely a hallucinogen: it is today the psychedelic most advanced in formal clinical research.

Duration and tolerance

The effect begins within 20 to 60 minutes, peaks around 1 to 2 hours, with a total duration of 4 to 6 hours, followed by a return phase of 1 to 2 hours. Lemon tek preparation tends to speed up onset (about 15 to 30 minutes), to make the peak sharper, and sometimes to shorten the duration.

Tolerance sets in rapidly, with cross-tolerance with LSD, N,N-DMT and other 5-HT2A agonists. A gap of at least one to two weeks is recommended to recover full intensity. Microdosing data remain mixed in controlled trials.

Harm reduction

Psilocybin can cause anxiety, confusion, bad trips or nausea. A history of psychosis or bipolar I disorder is a major contraindication. Several interactions are described: lithium, tramadol and MAOIs increase the risk, while SSRIs may attenuate the effect. HPPD (persistent perception disorder) is rare but documented. Set and setting are essential, especially at high doses. In the case of wild foraging, there is a risk of confusion with toxic species (for example Galerina marginata).

The potency of psilocybin mushrooms varies greatly depending on the species and the specimen. Mesoamerican ritual use is ancient (María Sabina, popularised by Wasson in 1957 and Hofmann in 1958). On the legal side, Oregon has offered supervised services since 2023, and Australia has authorised supervised therapeutic use for treatment-resistant depression since 2023.

Sources

• Griffiths et al. (2006), modern foundation of the research programme on the mystical experience
• Carhart-Harris, Davis, Ross, Johnson, clinical data (depression, end-of-life anxiety, addictions)
• FDA Breakthrough Therapy designation: COMPASS / COMP360 (2018, treatment-resistant depression) and Usona (2019, major depressive disorder)
• María Sabina, R. Gordon Wasson (1957) and Albert Hofmann (1958), ritual use and identification of psilocybin
• Work on the reduction of DMN activity and brain entropy under psilocybin