[31] 6,000-year-old pictographs discovered near the Spanish town of Villar del Humo illustrate several mushrooms that have been tentatively identified as Psilocybe hispanica, a hallucinogenic species native to the area.

According to the Dominican friar Diego Durán in The History of the Indies of New Spain (published c. 1581), mushrooms were eaten in festivities conducted on the occasion of Aztec emperor Moctezuma II's accession to the throne in 1502.

[38]: 10–12  The first reliably documented report of intoxication with Psilocybe semilanceata—Europe's most common and widespread psychedelic mushroom—involved a British family in 1799, who prepared a meal with mushrooms they had picked in London's Green Park.

Hofmann—who had synthesized lysergic acid diethylamide (LSD) in 1938—led a research group that isolated and identified the psychoactive alkaloids psilocybin and psilocin from Psilocybe mexicana, publishing their results in 1958.

[2] In the early 1960s, Harvard University became a testing ground for psilocybin through the efforts of Timothy Leary and his associates Ralph Metzner and Richard Alpert (who later changed his name to Ram Dass).

[45] In 1970, Congress passed "The Federal Comprehensive Drug Abuse Prevention and Control Act" that made LSD, peyote, psilocybin, and other hallucinogens illegal to use for any purpose, including scientific research.

[48]: 276  This was due in large part to wide dissemination of information on the topic, which included works such as those by Carlos Castaneda and several books that taught the technique of growing psilocybin mushrooms.

The new technique involved the use of ordinary kitchen implements, and for the first time the layperson was able to produce a potent entheogen in his own home, without access to sophisticated technology, equipment or chemical supplies.

[50] Because of lack of clarity about laws concerning psilocybin mushrooms, specifically in the form of sclerotia (also known as "truffles"), in the late 1990s and early 2000s European retailers commercialized and marketed them in smartshops in the Netherlands, the UK, and online.

Advances in neuropharmacology and neuropsychology and the availability of brain imaging techniques have provided impetus for using drugs like psilocybin to probe the "neural underpinnings of psychotic symptom formation including ego disorders and hallucinations".

[55] After ingesting psilocybin, the user may experience a wide range of emotional effects which can include: feelings of disorientation, lethargy, giddiness, euphoria, joy, and depression.

[60]: 175  At higher doses, psilocybin can lead to "intensification of affective responses, enhanced ability for introspection, regression to primitive and childlike thinking, and activation of vivid memory traces with pronounced emotional undertones".

A common adverse effect resulting from psilocybin mushroom use involves "bad trips" or panic reactions, in which affected individuals become anxious, confused, agitated, or disoriented.

[3] Likewise, a 2010 Dutch study ranked the relative harm of psilocybin mushrooms compared to a selection of 19 recreational drugs, including alcohol, cannabis, cocaine, ecstasy, heroin, and tobacco.

[110]: 13  Psychedelic researcher Rick Doblin considered the study partially flawed due to incorrect implementation of the double-blind procedure, and several imprecise questions in the mystical experience questionnaire.

[110]: 24  This sentiment was echoed by psychiatrist William A. Richards, who in a 2007 review stated "[psychedelic] mushroom use may constitute one technology for evoking revelatory experiences that are similar, if not identical, to those that occur through so-called spontaneous alterations of brain chemistry.

[115] A follow-up study conducted 14 months after the original psilocybin session confirmed that participants continued to attribute deep personal meaning to the experience.

[56][92] While many recent studies have concluded that psilocybin can cause mystical-type experiences having substantial and sustained personal meaning and spiritual significance, not all the medical community agree.

The psilocybin present in certain species of mushrooms can be ingested in several ways: by consuming fresh or dried fruit bodies, by preparing an herbal tea, or by combining with other foods to mask the bitter taste.

[121] Structural analogues of psilocybin (4-PO-DMT; O-phosphorylpsilocin) and psilocin (4-HO-DMT) include dimethyltryptamine (DMT), 5-hydroxytryptamine (5-HT), bufotenin (5-HO-DMT), 4-AcO-DMT (psilacetin; O-acetylpsilocin), 4-PrO-DMT (O-propionylpsilocin), psilomethoxin (4-HO-5-MeO-DMT; 5-methoxypsilocin), ethocybin (4-PO-DET), baeocystin (4-PO-NMT), aeruginascin (4-PO-TMT), and norbaeocystin (4-PO-T), among others.

[124] The sequence of the intermediate steps has been shown to involve four enzymes (PsiD, PsiH, PsiK, and PsiM) in P. cubensis and P. cyanescens, although it is possible that the biosynthetic pathway differs between species.

[145][14][10][101][89] Activation of serotonin 5-HT2A receptors in layer V of the medial prefrontal cortex (mPFC) and consequent glutamate release in this area has been especially implicated in the hallucinogenic effects of psilocybin and other serotonergic psychedelics.

[101] Serotonin 5-HT2C receptor activation and downstream inhibition of the mesolimbic dopamine pathway may be involved in the limited addictive potential of serotonergic psychedelics like psilocybin.

Although the earliest methods commonly used gas chromatography, the high temperature required to vaporize the psilocybin sample prior to analysis causes it to spontaneously lose its phosphoryl group and become psilocin—making it difficult to chemically discriminate between the two drugs.

In forensic toxicology, techniques involving gas chromatography coupled to mass spectrometry (GC–MS) are the most widely used due to their high sensitivity and ability to separate compounds in complex biological mixtures.

[215] A 2009 publication reported using HPLC to quickly separate forensically important illicit drugs including psilocybin and psilocin, which were identifiable within about half a minute of analysis time.

The majority of these are found in Mexico (53 species), with the remainder distributed in the United States and Canada (22), Europe (16), Asia (15), Africa (4), and Australia and associated islands (19).

[219][125] In general, psilocybin-containing species are dark-spored, gilled mushrooms that grow in meadows and woods of the subtropics and tropics, usually in soils rich in humus and plant debris.

The Advanced Integrative Medicine Science (AIMS) Institute in concert with the NPA filed a series of lawsuits seeking both the rescheduling of and expanded right-to-try access to psilocybin.

[30][267][280] A potential risk of frequent repeated use of psilocybin and other serotonergic psychedelics for psychiatric disorders is cardiac fibrosis and valvulopathy caused by serotonin 5-HT2B receptor activation.