Inflammation and Regeneration Vol.29 No.1 JANUARY 2009 47 Review Article Historical overview of psychoactive mushrooms Yoshihiro Matsushima1), Fumio Eguchi1, ＊), Tadahiro Kikukawa1), and Takahide Matsuda2) 1)Department of Health and Nutrition, Takasaki University of Health and Welfare, Gunma, Japan 2)Division of General Internal Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan Humans have used psychoactive mushrooms for medical, recreational, religious and ritual purposes since pre-history. Previous studies have clarified that psychoactive mushrooms produce psychoactive agents such as psilocybin, psilocin, ibotenic acid, and muscimol. However, the status of psychoactive mushrooms in most countries as illegal hallucinogens has prevented full investigation of their biochemical properties. Recent studies have shown that many psychoactive agents pass through the blood-brain barrier and act on neu- rotransmitter receptors. Psilocybin and psilocin are 5-HT1A and 5-HT2A/C receptor agonists, respectively, while ibotenic acid is a glutamic acid receptor agonist and muscimol is a GABAA receptor agonist. A new psychoac- tive agent, aeruginascin, has also been isolated from psychoactive mushrooms, and it is expected that more useful compounds will be discovered as the technology of component analysis advances. In addition, it has been shown that psilocybin and psilocin have high therapeutic efficiency for obsessive-compulsive disorder, which is a difficult-to-treat nervous disease. The increase of nervous diseases in modern society has thus given new importance to psychoactive mushrooms. In this review, we summarize the history of the use of psychoactive mushrooms, from pre-history to the modern age, describe their classification and distribution, survey previous studies, and discuss their therapeutic effects for difficult-to-treat nervous disease. The utiliza- tion and distribution of psychoactive mushrooms in Japan is given special attention, as there are few articles on this subject. Rec.7/23/2008, Acc.9/5/2008, pp47-58 ＊Correspondence should be addressed to: Fumio Eguchi, Department of Health and Nutrition. Faculty of Health and Welfare, Takasaki University of Health and Welfare 37-1, Nakaorui, Takasaki, Gunma 370-0033, Japan. Phone: +81-27-352-1290, Fax: +81-27-353-2055, e-mail: [email protected] KKKey wey wooordsrdsrds psychoactive mushrooms, psilocybin, psilocin Introduction ample, has earned recognition as mental disease only recently. Recently, the increasing number of people suffering from As this phenomenon is likely to continue for the foreseeable fu- mental disease has become a serious social problem. Addition- ture, it is likely that psychiatric studies will grow in importance, ally, not only the number but also the range of disorders has as further investigation of the link between the mind and body been increasing; obsessive-compulsive disorder (OCD), for ex- will be needed. Presented by Medical*Online 48 炎症・再生 Review Article HistoricalVol.23 overview No.1 of 2003psychoactive mushrooms Fig.1 Distribution map of psy- choactive mushrooms ha- bitants Light gray countries: 1-5 reports of psy- choactive, Gray countries: 6-15 reports of psychoactive mushrooms, Black countries: more than 15 reports of psy- choactive mushrooms Humans have used psychoactive mushrooms for medical use today1,2). Mushroom poisonings are roughly grouped into the (physical and mental), recreational, religious and ritual uses (as following four categories: protoplast poisoning, autonomic nerve tool for conversations with the inner self or God) since pre-his- poisoning, central nerve poisoning, and stomach and intestine tory. Similar to alcoholic beverages, psychoactive mushrooms poisoning. Psychoactive mushrooms poisonings belong in the have had a long and generally positive relationship with humans. category of central nerve poisoning. When ingested, the mush- Previous research has demonstrated that certain substances rooms cause central nervous symptoms, including hallucinations, passing through the blood-brain barrier affect the central ner- auditory hallucinations and mental alterations, as well as physi- vous system and cause hallucinogenic effects. Natural products cal symptoms including spasm, numbness, and intoxication. that have the ability to pass through the blood-brain barrier are These symptoms are expressed for 20 minutes to two hours after very valuable, and research on these substances is considered ingestion and are usually transient. increasingly important. Moreover, recent studies have shown that Guzman et al.(1998)3) divided psychoactive mushrooms into substances produced by psychoactive mushrooms are highly ef- four groups. fective for the treatment of intractable nervous diseases. Thus, The first group comprises mushrooms that produce psilocy- these mushrooms have potential value as a novel pharmaco- bin, psilocin, and their derivatives. Psilocybin and psilocin are therapy' or something similar. similar in structure to serotonin, an intracerebral neurotransmit- However, the number of comprehensive papers on psychoac- ter, and act on serotonin receptors in the brain to cause halluci- tive mushrooms is limited. In particular, for Japanese psychoac- nations. Many of the so-called called“magic mushrooms”used tive mushrooms, there has been no comprehensive report on the for recreational purposes belong to this group of psychoactive classification, history and previous studies of these mushrooms. mushrooms. The main genera include Psilocybe, represented by Hence, this article focuses on the history of the use of psychoac- Psilocybe cubensis and Psilocybe cyanescens Wakefield, and tive mushrooms to comprehensively summarize their classifica- Panaeolus, represented by Panaeolus papilionaceus and tion, distribution and active components, with an emphasis on Panaeolus sphinctrinus, Gymnopilus, Copelandia, Hyboloma, Japanese psychoactive mushrooms. Pluteus, Inocybe, Conocybe, and Panaeolina. The second group comprises mushrooms that produce ibotenic Classification and distribution acid and muscimol. Ibotenic acid is a non-protein amino acid Psychoactive mushrooms are generally classified as poison- with an isoxazole skeleton and acts as an agonist to glutamic ous mushrooms. Lincoff and Michell developed a classification acid. Ibotenic acid is decarboxylated to muscimol, which acts as method for mushroom poisonings in 1977 which is still in wide an agonist to GABA (gamma-aminobutyric acid). Mushrooms Presented by Medical*Online Inflammation and Regeneration Vol.29 No.1 JANUARY 2009 49 Table 1 Species of Japanese psychoactive mushrooms of the second group belong to genus Amanita, represented by rooms habitants. Psychoactive mushrooms are distributed nearly Amanita muscaria and Amanita pantherina. However, A. worldwide, with reports published in Canada, the U.S. (particularly pantherina and A. muscaria produce not only ibotenic acid and the Northwest and Northeast), Mexico, South America, Europe, muscimol but also other poisons, often causing complex poison- India, Japan, New Guinea, and Australia (particularly the east- ing symptoms by several agents. ern part). Indigenous peoples in these regions are said to have The third group is made up of the genus Claviceps, which traditionally used psychoactive mushrooms. produces ergot alkaloids and is represented by Claviceps purpurea, and the genus Cordyceps. The fourth group has been Japanese psychoactive mushrooms subjected to neither credible chemical research nor the identifi- Numerous psychoactive mushrooms that inhabit Japan, includ- cation of its active components. Several species of Psilocybe ing the 30 species listed below (Table 1), and this number is and Russula belong to this group, and some members (as well as projected to increase further as research advances. In addition, many species of Amanita) produce serotonin, baeocystine, P. cubensis, whose culture kits have widely been distributed, was norbaeosystine and bufotenine, indole alkaloids derived from confirmed to grow wild in Japan4). There is concern that the preva- tryptophane, from which psilocybin and psilocin are also derived. lence of ready-to-culture, exotic species of psychoactive mush- The figure below (Fig.1) is based on a report by Guzman et al. rooms will affect the ecological status of indigenous species in (1998)3) and shows a distribution map of psychoactive mush- Japan. Presented by Medical*Online 50 Review炎症・再生 Article HistoricalVol.23 overview No.1 of psychoactive2003 mushrooms Most psychoactive mushrooms that have been non-purposely in Scandinavia, morphological similarity and the abundance of ingested in Japan are A. pantherina and Psilocybe argentipes19). mycorrhiza-forming white birch and pine trees, Kaplan (1975)24) However, the number of mushroom poisonings due to uninten- proposed that the mushrooms depicted was A. muscaria, a psy- tional ingestion is relatively small compared with the total num- choactive mushrooms. ber of mushroom poisonings in Japan, with no confirmed cases Numerous Mayan artifacts known as“mushroom stones” of death11,20). have been discovered throughout modern Guatemala in Central Musha et al.(1986)21), (1988)22) reported detailed records of and South America. These stones are mushroom-shaped icons poisoning by P. argentipes which inhabit only in Japan, and clas- approximately 30 cm high, with human and animal carvings in sified the symptoms into the following three groups: physical the grip, and are thought to date to the