Psilocybin

Psilocybin is a psychedelic drug, with mind-altering effects similar to those of LSD and mescaline. The effects can include altered thinking processes, perceptual distortions, an altered sense of time, and spiritual experiences, as well as adverse reactions such as nausea and panic attacks. Psilocybin is produced by over 200 species of mushrooms. The most potent are members of the genus Psilocybe, such as P. cubensis, P. semilanceata, and P. cyanescens, but psilocybin has also been isolated from about a dozen other genera, collectively known as psilocybin mushrooms.

In Mexico, Central America, and South America, psilocybin-containing mushrooms have been ingested for thousands of years, primarily for spiritual purposes. In a 1957 Life magazine article, R. Gordon Wasson described his experiences ingesting psilocybin-containing mushrooms during a traditional ceremony in Mexico, introducing the drug to popular culture. Shortly afterward the Swiss chemist Albert Hofmann was able to purify the active principle psilocybin from the mushroom Psilocybe mexicana, and developed a synthetic method to produce the drug. Hofmann's employer Sandoz marketed and sold pure psilocybin to physicians and clinicians worldwide for use in psychedelic psychotherapy.

Enthusiasts for the drug consider it an entheogen (spirituality-enhancing agent) and a tool to supplement practices for transcendence, including meditation and psychonautics. The intensity and duration of the effects of psilocybin is variable, depending on species or cultivar of mushrooms, dosage, individual physiology, and set and setting, as was shown in experiments led by Timothy Leary at Harvard University in the early 1960s. Once ingested, psilocybin is rapidly metabolized to psilocin, which then acts on serotonin receptors in the brain. The mind-altering effects of psilocybin typically last from two to six hours; however, to individuals under the influence of psilocybin, the effects may seem to last much longer, since the drug can distort the perception of time. Psilocybin has a low toxicity, and reports of lethal doses from ingestion of the drug are rare. Several modern bioanalytical methods have been adapted to rapidly and accurately screen the levels of psilocybin in mushroom samples and body fluids. Possession of psilocybin-containing mushrooms has been outlawed in most countries, and it has been classified as Schedule I by many national drug laws.

History
There is evidence to suggest that psychoactive mushrooms have been used by man in religious ceremonies for millennia. Rock art discovered near the town of Villar del Humo in Spain offers evidence that Psilocybe hispanica was used in religious rituals 6000 years ago; similarly, murals dated 7000 to 9000 BCE found in the Sahara desert in southeast Algeria suggest prehistoric usage of psilocybin mushrooms. In the Mayan and Aztec cultures, psilocybin mushrooms were used for rituals and ceremonies; in Nahuatl, the language of the Aztecs, the mushrooms were called teonanacatl, or "God's flesh". Following the arrival of Spanish explorers to the New World in the 16th century, chroniclers reported the use of mushrooms by the natives for ceremonial and religious purposes. According to the Dominican friar Diego Durán in The History of the Indies of New Spain (published circa 1581), mushrooms were eaten in festivities conducted on the occasion of the accession to the throne of Aztec emperor Moctezuma II in 1502. The Franciscan friar Bernardino de Sahagún wrote of witnessing mushroom usage in his Florentine Codex (1545–1590). In the following passage, he described how some merchants would celebrate upon returning from a successful business trip: "Coming at the very first, at the time of feasting, they ate mushrooms when, as they said, it was the hour of the blowing of the flutes. Not yet did they partake of food; they drank only chocolate during the night. And they ate mushrooms with honey. When already the mushrooms were taking effect, there was dancing, there was weeping.... Some saw in a vision that they would die in war. Some saw in a vision that they would be devoured by wild beasts.... Some saw in a vision that they would become rich, wealthy. Some saw in a vision that they would buy slaves, would become slave owners. Some saw in a vision that they would commit adultery [and so] would have their heads bashed in, would be stoned to death.... Some saw in a vision that they would perish in the water. Some saw in a vision that they would pass to tranquillity in death. Some saw in a vision that they would fall from the housetop, tumble to their death ... All such things they saw.... And when [the effects of] the mushroom ceased, they conversed with one another, spoke of what they had seen in the vision.'" After the defeat of the Aztecs, the Spanish conquerors forbade traditional religious practices and rituals, and ceremonial mushroom use was driven underground. The American banker and amateur ethnomycologist R. Gordon Wasson and his wife Valentina studied the ritual use of psychoactive mushrooms by the native population in the Mazatec village Huautla de Jiménez. In 1957, they published an article in Life magazine (Seeking the Magic Mushroom) in which they described the occurrence of hallucinatory experiences during these rituals. Later the same year they were accompanied on a followup expedition by the French mycologist Roger Heim, who identified several of the mushrooms as Psilocybe species. Heim was able to cultivate the mushrooms in France, and sent samples for analysis to the chemist Albert Hofmann, who was working for the Swiss multinational pharmaceutical company Sandoz (now Novartis). Hofmann, who had in 1938 created LSD, was the first to recognize the importance and chemical structure of the pure compounds he called psilocybin and psilocin. Leading a research group that was able to isolate and identify the compounds from Psilocybe mexicana,  Hofmann was aided in the discovery process by his willingness to ingest mushroom extracts. He and his colleagues later synthesized a number of compounds chemically related to the naturally occurring psilocybin: "In essence, these were the same molecules except that: (1) the phosphoryl or hydroxy group at the top of the indole ring was moved around to other ring positions, and (2) different numbers of methyl groups (CH3) and other carbon chains were added to the side-chains and to the nitrogen on the indole ring to see how these changes would affect psychoactivity."

Two diethyl (containing two ethyl groups in place of the two methyl groups) analogs of psilocybin and psilocin were synthesized by Hofmann, 4-phosphoryloxy-N,N-diethyltryptamine, called CEY-19, and 4-hydroxy-N,N-diethyltryptamine, called CZ-74. Because their physiological effects last only about three and a half hours (compared to roughly double that with psilocybin), they proved more manageable in European clinics using "psycholytic therapy"—a form of psychotherapy that advocates the controlled use of psychedelic drugs. Sandoz marketed and sold pure psilocybin under the name Indocybin to physicians and clinicians worldwide. There were no reports of serious complications when psilocybin was used in this way.

In the early 1960s, Harvard University became a testing ground for psilocybin, through the efforts of Timothy Leary and his associate Richard Alpert (who later changed his name to Ram Dass). Leary was able to obtain synthesized psilocybin from Hofmann through Sandoz pharmaceutical. Although some studies in the early 1960s demonstrated positive results using psilocybin in clinical psychiatry, the backlash against LSD usage swept psilocybin along with it into the Schedule I category of illicit drugs in 1970. Rules were introduced to restrict the use of the drug in human research, and scientists who worked with the drug faced reduced funding and being "professionally marginalized". Despite the legal restrictions on psilocybin use, the 1970s witnessed the emergence of psilocybin as the "entheogen of choice". This was due in large part to a wide dissemination of information on the topic, which even included works such as those by Carlos Castaneda, and several books that taught the technique of growing psilocybin mushrooms. One of the most popular of these books was produced under the pseudonyms O.T. Oss and O.N. Oeric by Jeremy Bigwood, Dennis J. McKenna, K. Harrison McKenna, and Terence McKenna, entitled Psilocybin: Magic Mushroom Grower's Guide. Over 100,000 copies had been sold by 1981. As ethnologist Jonathan Ott explains, "These authors adapted San Antonio's technique (for producing edible mushrooms by casing mycelial cultures on a rye grain substrate; San Antonio 1971) to the production of Psilocybe [Stropharia] cubensis. 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."

Because of a lack of clarity about laws about psilocybin mushrooms, retailers in the late 1990s and early 2000s commercialized and marketed them in smartshops in the Netherlands and the UK, and on the internet. Several websites emerged that have contributed to the accessibility of information on description, use, effects and exchange of experiences among users. Since 2001, six EU countries have tightened their legislation on psilocybin mushrooms in response to concerns regarding their prevalence and increasing usage. In recent years, psilocybin and its effects on human consciousness has again become the subject of scientific study.

Occurrence
Psilocybin is a naturally occurring compound found in varying concentrations in over 200 species of Basidiomycota mushrooms. According to the 1998 review on the worldwide distribution of hallucinogenic mushrooms by Gastón Guzmán and colleagues, these species are distributed amongst the following genera: Psilocybe (116 species), Gymnopilus (14), Panaeolus (13), Copelandia (12), Hypholoma (6), Pluteus (6) Inocybe (6), Conocybe (4), Panaeolina (4), Gerronema (2) and Agrocybe, Galerina and Mycena (1 species each). 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. Psilocybin mushrooms occur on all continents, but the majority of species are found in subtropical humid forests. Roughly 40% of the world's known psychoactive mushroom species are found in Mexico. Although the presence or absence of psilocybin is not of much use as a chemotaxonomical marker at the familial level or higher, it is used to classify taxa of lower taxonomic groups.

Mushroom caps tend to contain more of the psychoactive compounds than the stems. The spores of these mushrooms do not contain psilocybin or psilocin. The total potency varies greatly between species and even between specimens of one species in the same batch. Younger, smaller mushrooms have a higher concentration of psilocybin than larger, mature mushrooms. In general, the psilocybin content of mushrooms is quite variable (ranging from almost nothing to 1.5% of the dry weight) and depends on species, growth and drying conditions, and mushroom size. Psilocybin is more stable in dried than fresh mushrooms. Mature mycelia contains some psilocybin, while young mycelia (recently germinated from spores) does not contain appreciable amounts of psilocybin. Many species of mushrooms containing psilocybin also contain small amounts of the psilocybin analogs baeocystin and norbaeocystin,  chemicals thought to be biogenic precursors. Most species of psilocybin-containing mushrooms bruise blue when handled or damaged due to the oxidization of phenolic compounds. This reaction, however, is not a definitive method of identification or determining a mushroom's potency.

Chemistry
Psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine or 4-PO-DMT; alternatively spelled psilocybine ) is a prodrug that is converted into the pharmacologically active compound psilocin in the body by a dephosphorylation reaction. This chemical reaction takes place under strongly acidic conditions, or under physiological conditions in the body, through the action of enzymes called phosphatases. Oxidization of psilocin by the enzyme hydroxyindole oxidase yields the deep blue-colored compound ortho-quinone. This compound readily undergoes electron transfer, a chemical feature that contributes to the biochemical effects of psilocybin.

Psilocybin is a tryptamine compound having a chemical structure derived from the amino acid tryptophan and containing a ring configuration called an indole linked to an ethylamine substituent; psilocybin bears a close structural resemblance to the neurotransmitter serotonin (5-hydroxytryptamine). Biosynthetically, the biochemical transformation from tryptophan to psilocybin involves several enzyme reactions: decarboxylation, methylation at the N9 position, 4-hydroxylation, and O-phosphorylation. Isotopic labeling experiments suggest that tryptophan decarboxylation is the first biosynthetic step and that O-phosphorylation is the final step. The precise sequence of the intermediate steps is not known with certainty, and the biosynthetic pathway may differ between species.

Psilocybin is a zwitterionic alkaloid that is soluble in water, moderately soluble in methanol and ethanol, and insoluble in most organic solvents. Exposure to light is detrimental to the stability of aqueous solutions of psilocybin, and will cause it to rapidly oxidize—an important consideration when using it as an analytical standard. A method for the large-scale synthesis of psilocybin without chromatographic purification was reported by a Japanese group in 2003. The method, which starts with 4-hydroxyindole, generates psilocybin from psilocin at an 85% yield, a marked improvement over yields reported from previous syntheses. Purified psilocybin is a white, needle-like crystalline powder with a melting point between 190 –.

Analytical methods
Several relatively simple chemical tests—commercially available as reagent testing kits—can be used to detect the presence of psilocybin. The drug reacts in the Marquis test to produce a yellow color, and a green color in the Mandelin test. Ehrlich's reagent and DMACA reagent are used as sprays to detect the drug after thin layer chromatographic analysis. Many modern analytical techniques have been adapted to identify and evaluate the quantity of psilocybin in mushroom material. The earliest techniques used gas chromatography; however, a problem with this method is that psilocybin dephosphorylates to psilocin prior to analysis, making it difficult to 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. These techniques include ion mobility spectrometry, capillary zone electrophoresis, ultraviolet spectroscopy, and infrared spectroscopy. High performance liquid chromatography (HPLC) has been used with ultraviolet, fluorescence, electrochemical, or electrospray mass spectrometric detection methods.

Various chromatographic methods have been developed to detect psilocin in body fluids: the rapid emergency drug identification system (REMEDi HS), a drug screening method based on HPLC; HPLC with electrochemical detection; GC-MS;  and liquid chromatography coupled to mass spectrometry. Although the determination of psilocin levels in urine can be performed without sample clean-up, the analysis in plasma or serum requires a preliminary extraction, followed by derivatization of the extracts in the case of GC-MS. A specific immunoassay has also been developed to detect psilocin in whole blood samples. A 2009 publication reported using HPLC to obtain a high-speed separation of forensically important illicit drugs including psilocybin and psilocin, which were identifiable within 0.5 min of analysis.

Pharmacology
Psilocybin is rapidly dephosphorylated in the body to psilocin, which then acts as a partial agonist to several receptors involved with the neurotransmission of serotonin. Psilocin has a high affinity for the 5-HT2A serotonin receptor in the brain, where it mimics the effects of serotonin (5-HT). Psilocin binds less tightly to other serotonergic receptors 5-HT1A, 5-HT1D, and 5-HT2C. Serotonin receptors are located in numerous parts of the brain including the cerebral cortex, and are involved in a wide range of functions, including regulation of mood and motivation. The psychotomimetic effects of psilocin can be blocked in a dose-dependent fashion by the 5-HT2A antagonist drugs ketanserin and risperidone. Although the 5-HT2A receptor is responsible for most of the effects of psilocybin, various lines of evidence have shown that interactions with non-5-HT2A receptors also contribute to the subjective and behavioral effects of the drug.

The chemical structures of psilocybin and related analogs have been used in computational biology to help model the structure, function, and ligand-binding properties of the 5-HT2C G-protein-coupled receptor. In contrast to LSD, psilocybin and psilocin have no affinity for the dopamine D2 receptor.

Toxicity
The toxicity of psilocybin is low; in rats, the oral is 280 mg/kg, approximately one and a half times that of caffeine. When administered intravenously in rabbits, psilocybin's LD50 is approximately 12.5 mg/kg (rabbits, however, are extremely intolerant to the effects of most psychoactive drugs). The Registry of Toxic Effects of Chemical Substances gives psilocybin a relatively high therapeutic index of 641 (higher values correspond to a better safety profile); for comparison, the therapeutic indexes of aspirin and nicotine are 199 and 21, respectively. The lethal dose from psilocybin toxicity alone is unknown at recreational or medicinal levels, and has rarely been documented—only two cases attributed to overdosing on hallucinogenic mushrooms have been reported in the literature. Psilocybin makes up roughly 1% of the weight of Psilocybe cubensis mushrooms, and so nearly 1.7 kilograms of dried mushrooms, or 17 kilograms of fresh mushrooms, would be required for a 60 kg person to reach the 280 mg/kg LD50 rate of rats. Although experiments with mice have shown no evidence that the drug causes birth defects, it is recommended that pregnant women avoid its usage.

Physiology
Psilocybin is absorbed through the lining of the mouth and stomach. Effects begin 10–40 minutes after ingestion of psilocybin-containing mushrooms, and last from 2–6 hours depending on dose, species, and individual metabolism. A typical recreational dosage is from 10–50 mg psilocybin, although only 4–10 mg (corresponding roughly to 50–300 micrograms per kilogram of body weight) are required to induce hallucinogenic effects. However, a very small number of people are unusually sensitive to psilocybin's effects, such that a normally threshold-level dose of around 2 mg of psilocybin can result in effects usually associated with medium or high doses. Conversely, there are some people who require relatively high doses of psilocybin to get noticeable effects. Individual brain chemistry and metabolism play a large role in determining a person's response to psilocybin. Psilocybin is metabolized mostly in the liver, where it becomes psilocin, which is broken down by the enzyme monoamine oxidase to produce several metabolites that can circulate in the blood plasma, including 4-hydroxyindole-3-acetaldehyde, 4-hydroxytryptophol, and 4-hydroxyindole-3-acetic acid. Some psilocin is not broken down by enzymes, and instead forms a glucuronide; this is a biochemical mechanism animals use to eliminate toxic substances by linking them with glucuronic acid, which can then be excreted in the urine. Psilocin concentrations in the plasma of adult volunteers averaged about 8 µg/L within 2 hours after ingestion of a single 15 mg oral psilocybin dose; psychological effects occur with a blood plasma concentration of 4–6 µg/L. Psilocybin is about 100 times less potent than LSD on a weight-per-weight basis, and the physiological effects last about half as long.

Tolerance to psilocybin builds and dissipates quickly; ingesting psilocybin more than about once a week can result in diminished effects. Tolerance dissipates after a few days, so doses can be spaced several days apart to avoid the effect. Studies have demonstrated that a cross-tolerance can develop between psilocybin and the pharmacologically similar LSD; further, cross-tolerance also develops between psilocybin and phenylethylamine hallucinogens such as mescaline and 2,5-dimethoxy-4-methylamphetamine. MAO inhibitors (MAOI) have been known to sustain the effects of psilocybin for longer periods of time; people who are taking an MAOI for a medical condition may experience highly potentiated effects. Acetaldehyde, one of the primary breakdown metabolites of consumed alcohol, reacts with biogenic amines present in the body to produce MAOIs related to tetrahydroisoquinoline and β-carboline, and thus enhance the psychoactive effects of psilocybin. A similar effect has been suggested for tobacco users.

Repeated use of psilocybin does not lead to physical dependence on the drug. A 2008 study concluded that, based on US data from the period 2000–2, adolescent-onset (defined here as ages 11–17) usage of hallucinogenic drugs (including psilocybin) did not increase the risk of drug dependence in adulthood; this was in contrast to adolescent usage of cannabis, cocaine, inhalants, anxiolytic medicines, and stimulants, all of which were associated with "an excess risk of developing clinical features associated with drug dependence".

Effects
The effects of psilocybin are highly variable and depend on the mindset and environment in which the user has the experience, factors commonly referred to as set and setting. In the early 1960s, Timothy Leary and colleagues at Harvard University investigated the role of set and setting on the effects of psilocybin. They administered the drug to 175 subjects from various backgrounds in a warm, supportive environment free from distractions, intended to be similar to a comfortable living room. Ninety-eight of the subjects were given questionnaires to assess their experiences and the contribution of background and situational factors. Individuals who had experience with psilocybin prior to the study reported more pleasant experiences than those for whom the drug was novel. Group size, dosage, preparation, and expectancy were important determinants of the drug response. Subjects placed in groups of more than eight individuals generally felt that the groups were less supportive, and their experiences were less pleasant. Conversely, smaller groups (fewer than six individuals) were seen as more supportive and subjects reported having more positive reactions to the drug. Leary and colleagues proposed that psilocybin heightens suggestibility, making an individual more receptive to interpersonal interactions and environmental stimuli. These findings were corroborated in a later review by Jos ten Berge (1999), who concluded that dosage, set, and setting were fundamental factors in determining the outcome of experiments that tested the effects of psychedelic drugs on artists' creativity.

After ingesting psilocybin, a typical subject initially feels somewhat disoriented, lethargic, and euphoric (but sometimes depressed instead). Pupil dilation and increases in heart rate are common. The drug can also cause temporary increases in blood pressure, which may be a risk factor for users with hypertension. At low doses, hallucinatory effects may occur, including enhancement of colors and the animation of geometric shapes. Closed-eye hallucination may occur, in which the affected individual sees multi-colored geometric shapes and vivid imaginative sequences. Some individuals report experiencing synesthesia, such as tactile sensations when viewing colors. At higher doses, hallucinatory effects increase and experiences tend to be less social and more introspective or entheogenic. Open-eye visuals are more common, and may be very detailed although rarely confused with reality. Based on a study of 27 hospital admissions of patients (ages ranging from 12 to 24 years) who consumed Psilocybe semilanceata, a 1980 clinical report summarized the distribution of clinical symptoms of psilocybin overdose as follows: perceptual disorder (23 patients), pupil dilation (20), dysphoria (unpleasant mood) (13), hyperreflexia (twitching) (12), tachycardia (increased heart rate) (10), drowsiness (7), and euphoria (elation) (5). These clinical responses were similar to results obtained in several earlier studies in which pure psilocybin was administered to human volunteers. A 2005 magazine survey of club goers in the UK found that nausea or vomiting was experienced by over a quarter of those who had used hallucinogenic mushrooms in the last year, although this effect is caused by the mushroom rather than psilocybin itself.

A 2011 study by Roland R. Griffiths and colleagues suggests that using a single high dosage of psilocybin can change the personality of its users. Changes in personality were assessed using the Revised NEO Personality Inventory, which describes people's personalities according to five factors: neuroticism, extroversion, conscientiousness, agreeableness, and openness. In the study, about half of the participants—described as healthy, "spiritually active", and many possessing postgraduate degrees—showed an increase in the personality dimension of "openness". It is not known whether these results can be generalized to larger populations.

Perceptual distortions
Psilocybin is known to strongly influence the subjective experience of the passage of time. Studies have demonstrated that psilocybin significantly impaired subjects’ ability to reproduce time intervals longer than 2.5 seconds, impaired their ability to synchronize to inter-beat intervals longer than 2 seconds, and reduced their preferred tapping rate. These results are consistent with the drug's role in affecting prefrontal cortex activity, and the role that the prefrontal cortex is known to play in time perception.

Users having a pleasant experience can feel an ecstatic sense of connection to others, nature, and the universe; other perceptions and emotions are also often intensified. Users having an unpleasant experience (a "bad trip") describe a reaction accompanied by fear, other unpleasant feelings, and occasionally by dangerous behavior. In general, "bad trip" is used to describe a reaction that is characterized primarily by fear or other unpleasant emotions, not just transitory experience of such feelings. A variety of factors may contribute to a psilocybin user experiencing a bad trip, including "tripping" during an emotional or physical low or in a non-supportive environment (see: set and setting). Ingesting psilocybin in combination with other drugs or with alcohol can also increase the likelihood of a bad trip. Other than the duration of the experience, the effects of psilocybin are similar to comparable dosages of LSD or mescaline. In the Psychedelics Encyclopedia, author Peter Stafford noted "The psilocybin experience seems to be warmer, not as forceful and less isolating. It tends to build connections between people, who are generally much more in communication than when they use LSD."

Mystical experiences
Psychedelic drugs can induce states of consciousness that have lasting personal meaning and spiritual significance in individuals who are religious or spiritually inclined; these states are called mystical experiences. Some researchers have proposed that many of the qualities of a drug-induced mystical experience are indistinguishable from genuine mystical experiences. In the late 1960s, Walter Pahnke and colleagues developed a set of categories to describe the common features of a mystical experience that was used as a basis of measurement for psychedelic drug experiences. In the Marsh Chapel Experiment, which was run by Walter Pahnke at the Harvard Divinity School under the supervision of Timothy Leary, almost all of the graduate degree divinity student volunteers who received psilocybin reported profound religious experiences. One of the participants was religious scholar Huston Smith, author of several textbooks on comparative religion; he later described his experience as "the most powerful cosmic homecoming I have ever experienced." In a 25-year followup to the experiment, all of the subjects given psilocybin described their experience as having elements of "a genuine mystical nature and characterized it as one of the high points of their spiritual life". 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. Nevertheless, he said that the study cast "a considerable doubt on the assertion that mystical experiences catalyzed by drugs are in any way inferior to non-drug mystical experiences in both their immediate content and long-term effects". 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."

In 2006, a group of researchers from Johns Hopkins School of Medicine led by Griffiths conducted an experiment to assess the degree of mystical experience and attitudinal effects of the psilocybin experience, using a modified version of the mystical experience questionnaire and a more rigorous double-blind procedure. As Griffiths said in an interview when asked about the similarity of his work with Leary's: "We are conducting rigorous, systematic research with psilocybin under carefully monitored conditions, a route which Dr. Leary abandoned in the early 1960s." The study has been praised by experts for the soundness of its experimental design. In the experiment, 36 volunteers without prior experience with hallucinogens were given psilocybin and methylphenidate (Ritalin) in separate sessions; the methylphenidate sessions served as a control and psychoactive placebo. The tests were double-blind. The degree of mystical experience was measured using a questionnaire on mystical experience developed by Ralph W. Hood; 61% of subjects reported a "complete mystical experience" after their psilocybin session, while only 13% reported such an outcome after their experience with methylphenidate. Two months after taking psilocybin, 79% of the participants reported moderately to greatly increased life satisfaction and sense of well-being. About 36% of participants also had a strong to extreme “experience of fear” or dysphoria (i.e., a “bad trip”) at some point during the psilocybin session (which was not reported by any subject during the methylphenidate session), with about one-third of these (13% of the total) reporting that this dysphoria dominated the entire session. These negative effects were reported to be easily managed by the researchers and did not have a lasting negative effect on the subject’s sense of well-being. Further measures at 14 months after the psilocybin experience confirmed that participants continued to attribute deep personal meaning to the experience.

Further studies by this group have investigated the relationship of psilocybin dose to likelihood of mystical experience in healthy volunteers. A double-blind study showed that psychedelic mushrooms could provide people an experience with substantial personal meaning and spiritual significance. In the study, one-third of the subjects reported that ingestion of psychedelic mushrooms was the single most spiritually significant event of their lives, and over two-thirds reported it among their five most meaningful and spiritually significant events. On the other hand, one-third of the subjects reported extreme anxiety. In a recent (2010) web-based questionnaire study designed to investigate user perceptions of the benefits and harms of hallucinogenic drug use, 60% of the 503 psilocybin users reported that their use of psilocybin had a long-term positive impact on their sense of well-being. In 2011, Griffiths and colleagues published the results of further studies designed to learn more about the optimum psilocybin doses needed for positive life-changing experiences, while minimizing the chance of negative reactions. In a 14 month followup, the researchers found that 94% of the volunteers rated their experiences with the drug as one of the top 5 most spiritually significant of their lives (44% said it was the single most significant). None of the 90 sessions that took place throughout the study were rated as decreasing well-being or life satisfaction. Moreover, 89% reported positive changes in their behaviors as a result of the experiences. The conditions of the experimental design included a single drug experience a month, on a couch, in a living-room-like setting, with eye shades and carefully chosen music (classical and world music). As an additional precaution to guide the experience, the 2011 study included a "monitor" whom the volunteers supposedly trusted. The monitors provided gentle reassurance when the volunteers experienced times of anxiety. The volunteers, monitors, and observers all remained blind to the exact dosages for the sake of the experiment.

Possible adverse psychiatric effects
Panic reactions can occur after consumption of psilocybin-containing mushrooms, especially if the ingestion is accidental or otherwise unexpected. For example, reactions such as violence, aggression, homicidal and suicidal attempts, prolonged schizophrenia-like psychosis, and convulsions have been reported in the literature. Consumption of psilocybin by schizophrenia patients can induce acute psychotic states requiring hospitalization. A 2005 survey found that almost a quarter of users in the past year had experienced a panic attack. Other adverse effects less frequently reported by psilocybin users include paranoia, confusion, derealization, disconnection from reality, and mania.

The similarity of psilocybin-induced symptoms to those of schizophrenia has led to the drug being used in both behavioral and neuroimaging studies of this psychotic disorder. In both cases, psychotic symptoms are thought to arise from a "deficient gating of sensory and cognitive information" in the brain that ultimately lead to "cognitive fragmentation and psychosis". There has been one case report of psilocybin and cannabis possibly causing hallucinogen persisting perception disorder (HPPD) (which at worst can last five years or more). However, the claimed association between HPPD and psychedelics is obscured by polydrug use and other variables.

Use in medicine
Psilocybin has been investigated as an experimental treatment for several disorders. In 1961, Timothy Leary and Richard Alpert ran the Harvard Psilocybin Project, carrying out a number of experiments concerning the use of psilocybin in the treatment of personality disorders and other uses in psychological counseling. In the late 1960s, in response to concerns regarding the proliferation of the unauthorized use of psychedelic drugs by the general public, psilocybin and other hallucinogenic drugs suffered negative press and faced increasingly restrictive laws; subsequently, authorized research into therapeutic applications of psychedelic drugs was repressed. In the 2000s, there has been a resurgence of research into the use of psychedelic drugs to explore the nature of the mystical experience, or for clinical applications, such as to address anxiety disorders, major depression, and various addictions.

A pilot study led by Francisco Moreno at the University of Arizona and supported by Multidisciplinary Association for Psychedelic Studies studied the effects of psilocybin on nine patients with obsessive-compulsive disorder (OCD). The study found that in a controlled clinical environment, psilocybin could be safely given to patients with OCD, and it was associated with substantial reductions in OCD symptoms in several of the patients. This effect may be caused by psilocybin's ability to reduce the levels of the serotonin-2A receptor, resulting in decreased responsiveness to serotonin and reduction of OCD symptoms. In addition, psilocybin has shown promise to ease the pain caused by cluster headaches, often considered not only the most painful of all types of headaches but "one of the worst pain syndromes known to mankind." In a 2006 study, most cluster headache patients who used psilocybin reported that the drug successfully aborted the attacks and extended the length of the remission period. Despite flaws in the study design, the results suggest that psilocybin merits further study for use in the prevention of cluster headaches—only subhallucinogenic doses of the drug are required for effective treatment, and no other medication has been reported to stop a cluster headache cycle.

Two current studies have investigated the possibility that psilocybin can ease the psychological suffering associated with cancer. One study, led by Charles Grob, involved 12 subjects with terminal cancer being administered the hallucinogen or a placebo in two separate sessions. A second study, led by Roland Griffiths at Johns Hopkins, administered psilocybin to people "with a current or past diagnosis of cancer who have some anxiety or are feeling down about their cancer". Preliminary results indicate that low doses of psilocybin can improve the mood and reduce anxiety of patients with advanced cancer, and that the effects last from two weeks to six months. In 2008, the Johns Hopkins research team published guidelines for responsibly conducting medical research trials with psilocybin and other hallucinogens in humans. These included recommendations on how to screen potential study volunteers to exclude those with personal or family psychiatric histories suggesting risk of averse reactions to hallucinogens.

Social and legal aspects
In the United States, psilocybin (and psilocin) were first subjected to federal regulation by a law that is commonly referred to as "the Drug Abuse Control Amendments of 1965". This law, a product of a bill sponsored by Senator Thomas J. Dodd, was passed in July 1965 and took effect on February 1, 1966. The law was an amendment to the federal Food, Drug and Cosmetic Act and was intended to regulate the unlicensed "possession, manufacture, or sale of depressant, stimulant and hallucinogenic drugs". The statutes themselves, however, did not list the "hallucinogenic drugs" that were being regulated. Instead the term "hallucinogenic drugs" was meant to refer to those substances that supposedly have a "hallucinogenic effect on the central nervous system".

Despite the seemingly strict provisions of the law, many people were exempt from prosecution. The statutes "permit[ted] … people to possess such drugs so long as they were for the personal use of the possessor, [for] a member of his household, or for administration to an animal". The federal law that specifically banned psilocybin and psilocin was enacted on October 24, 1968. The latter substances were said to have "a high potential for abuse", "no currently accepted medical use," and "a lack of accepted safety". On October 27, 1970, both psilocybin and psilocin became classified as Schedule I and were simultaneously labeled "hallucinogens" under a section of the “Comprehensive Drug Abuse Prevention and Control Act” known as the "Controlled Substances Act". Schedule I drugs are illicit drugs that are claimed to have no known therapeutic benefit. Parties to the treaty are required to restrict use of the drug to medical and scientific research under strictly controlled conditions. Most national drug laws have been amended to reflect this convention (for example, the US Psychotropic Substances Act, the UK Misuse of Drugs Act 1971, and the Canadian Controlled Drugs and Substances Act), with possession and use of psilocybin and psilocin being prohibited under almost all circumstances, and often carrying severe legal penalties.

Possession and use of psilocybin mushrooms, including the bluing species of Psilocybe, is therefore prohibited by extension. However, in many national, state, and provincial drug laws, there is a great deal of ambiguity about the legal status of psilocybin mushrooms and the spores of these mushrooms, as well as a strong element of selective enforcement in some places. In addition, there has been a general shift in attitudes regarding research with psilocybin and other hallucingenic agents; after a long moratorium on the use of these drugs, many countries are revising their positions and have started to approve studies to test the physiological and therapeutic effects of hallucinogens.

2006 Johns Hopkins experiment

 * "Hopkins Scientists Show Hallucinogen in Mushrooms Creates Universal 'Mystical' Experience", Johns Hopkins Medicine news release, July 11, 2006.
 * "Tripping Out: Scientists Study Mystical Effects of Mushrooms" by Joy Victory, Bharathi Radhakrishnan, and Andrea Carter, ABC News (online), July 11, 2006. ABC News video report of the study.

2008 Follow-up to Johns Hopkins experiment

 * "Spiritual Effects of Hallucinogens Persist, Johns Hopkins Researchers Report", Johns Hopkins Medicine news release, July 1, 2008.
 * "Sacred Intentions: Inside the Johns Hopkins Psilocybin Studies" by Michael M. Hughes, City Paper, October 8, 2008.

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