psilocybin (magic mushrooms)

see also:

• toxicology
• mushroom poisoning
• novel psychoactive substances (NPS)

• psilocybin “magic mushrooms” are often used as psychedelic hallucinogens with relatively short duration of effects although these can cause severe serious psychological adverse effects, and rarely respiratory paralysis
• there are hundreds of species belongings to at least 7 genera of psilocybin producing fungi
  • the genus Psilocybe is now estimated to contain over 300 species and is distributed worldwide
    • all described species, except the enigmatic secotioid Psilocybe weraroa, from New Zealand, are fungi which produce pileate-stipitate, agaricoid basidiomata (ie. a classic “toadstool” or mushroom structure: a cap and a central stalk, with spore-bearing gills or pores underneath) ¹⁾
    • salient macromorphological features for the majority of Psilocybe species include dark purple-brown basidiospores, the presence of an annulus that can be senescent, and blue bruising on the stipe, pileus, and mycelium upon contact
      • foragers generally identify them partly due to the presence of these purplish brown to black spores, white stems with absence of any orange, and blue bruising (the blue is not always present) but correct identification requires experience and perhaps no color blindness
• small numbers of treatments with psychedelic-assisted psychotherapy can potentially offer significant and sustained alleviation to symptoms of multiple psychiatric conditions

• active ingredients generally include varying proportions of:
  • psilocybin
    • 4-phosphoryloxy-N, N-dimethyltryptamine, an indole alkaloid structurally analogous to the neurotransmitter serotonin
    • when ingested, it is dephosphorylated to form the bioactive agent psilocin
    • Psilocybe species can vary in psilocybin content from 0.01 to 2.40% by dry weight
  • psilocin
    • usually present in much lower concentrations
    • in humans, binds to serotonin (5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, and 5-HT1D) receptors disrupting serotonergic neurotransmission producing physiological effects
  • baeocystin - precursor of psilocybin
• genetics and synthetic processes
  • there appears to be a cluster of five Psi genes in an ∼11–22 kilobase genomic region associated with psilocybin production from tryptophan²⁾
    • this gene cluster appears to have evolved in a common ancestor of Psilocybe and Gymnopilus
      • horizontal gene transfer (HGT) may have transferred these genes to some other species such as Conocybe, Panaeolus, and Pluteus
      • in addition convergent evolution of a different genetic psilocybin pathway and/or gene cluster has occurred at least twice in other species
    • tryptophan is decarboxylated by PsiD to form tryptamine which is then hydroxylated on the 4-position of the indole backbone by the cytochrome P-450 monooxygenase, PsiH, to form 4-hydroxytryptamine.
    • the hydroxyl group of 4-hydroxytryptamine is next phosphorylated by PsiK to form norbaeocystin.
    • iterative methylation of the amine by PsiM then forms baeocystin, and then psilocybin
    • psilocin is derived from the spontaneous dephosphorylation of psilocybin and can be converted back to psilocybin by PsiK
• some Psilocybe species also biosynthesize β-carbolines (e.g., harmane, harmine, norharmane), which inhibit the monoamine oxidase (MAO) family of enzymes responsible for degradation of serotonin, psilocybin, and related chemicals
  • the simultaneous production of β-carboline compounds in some Psilocybe species has been noted to differ between mycelia and mushrooms tissues
• the blue pigment is derived from linkage of psilocin monomers in damaged cells
  • the ecological function of psilocybin may be due to the potential toxicity of the oligomers that are produced upon injury

• Psilocybe cubensis - “golden tops”; main cultivated psilocybin species globally; grows on cattle or horse dung in Spring, Summer and Autumn, mainly in Queensland in Australia
• Psilocybe subcubensis - found in Autumn to early winter, esp. in Rhododendron or rose gardens
• conspecific species in Australia (ie. they are all the same species)³⁾⁴⁾:
  • Psilocybe subaeruginosa - “subs”; occasionally may cause fatal respiratory paralysis (see below), found on decaying wood from May to August
  • Psilocybe australiana - southern Australia around Sydney and in Tasmania usually in April
  • Psilocybe eucalypta - found in grassy areas near Eucalypt trees in eastern Australia, esp. NSW
  • Psilocybe tasmaniana - grows in April, May on dung (mainly kangaroo dung);
• Psilocybe coprophila - found in cow or horse dung, in temperate to subtropical regions
• Psilocybe semilanceata - “witch's hat”; “liberty cap”; found mainly in damp grasslands esp. where cows or sheep graze, mainly in May
• Gymnopilus purpuratus - “big gym”; “giant laughing mushroom”; southern Australia in May
• Panaeolus cyanescens - aka Copelandia cyanescens; eastern Australia
• perhaps other unidentified Psilocybe sp.

• the National Drug Strategy Household Survey from 2022–23 saw the percentage of Australians who used a psychedelic drug rise from 1.6 per cent in 2019 to 2.4 per cent three years later, taking the number of people who use these drugs annually up to about 500,000 people and 12.2% of those over aged 14 stated that they had used them at least once, up from 7.6% in 2001. ⁵⁾

• psilocin acts upon serotonin receptors
• psychoactive effects may be due to decreased activity and connectivity of some brain regions
• it appears to have the following actions:⁶⁾
  • can re-wire the brain
    • causes significant disruptions in brain functional connectivity (FC), particularly in the default mode network, linked to subjective experiences and lasting for weeks, which may underlie its therapeutic effects⁷⁾. Via serotonin 2A (5-HT2A) receptor activation, it can induce significant acute and persistent changes in self, time, and space perception.
    • can strengthen some connections and weaken others but this may be partly dependent upon what is being attended to during a session - one dose of psilocybin induced structural remodeling of dendritic spines in the medial frontal cortex in mice and its effect on connectivity is network specific, strengthening the routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops, and silencing a presynaptic region during psilocybin administration disrupts the rewiring. ⁸⁾ - hence this could be manipulated by third parties for better or worse
  • associated with decreases in cerebral blood flow and blood oxygen level dependent signaling
  • alters temporal processing

• although the risks and harms of psychedelics from a physical perspective are low, psychedelic drugs carry a unique psychological risk profile which is increased in uncontrolled settings.⁹⁾
• adverse experiences including feelings of loneliness, nightmares, anxiety, uncontrollable worrying, panic, despair, hallucinations, disorientation, derealization, suicidality, psychotic disorder, manic symptoms, cardiovascular events, and hallucinogen persisting perception disorder have been documented.
• adverse experiences such as anxiety and fear, existential struggle, social disconnection, depersonalization, and derealization can persist after psychedelic experiences, sometimes for over a year ¹⁰⁾
• vomiting was the most frequent reported adverse physical effect, with some respondents experiencing headaches, abdominal pain, and breathing difficulties;
• serotonin syndrome may occur when certain psychedelics are taken by those using specific antidepressant classes

• experienced users generally employ harm reduction or benefit enhancing strategies and these can be categorised into three themes¹³⁾:
  • before psychedelic use
    • mental preparation “set”
      • “embrace the experience and whatever you encounter on your journey”
      • “learn about psychedelic experiences/substance you are taking”
      • “clear time before and after for preparation and recovery”
      • “prepare for anxiety/challenge, whatever you are feeling will go away”
    • environment “setting”:
      • “be with people you love/trust” - this is particularly important if consuming “subs” which may cause paralysis and prevent calling for help
      • “have a guide/sitter/facilitator”
      • “be in a safe, familiar, and comfortable location ”
      • “music that will facilitate trip”
    • “start small (low doses)”
  • during psychedelic experience
    • “have water on hand and hydrate often”
  • after the experience (integration)