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Fungal Hallucinogens Psilocin, Ibotenic Acid, and Muscimol: Analytical Methods and Biologic Activities

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Fungal Hallucinogens Psilocin, Ibotenic Acid, and Muscimol: Analytical Methods and Biologic Activities REVIEW ARTICLE Fungal Hallucinogens Psilocin, Ibotenic Acid, and Muscimol: Analytical Methods and Biologic Activities Katarzyna Stebelska, PhD idea to use them for religious ceremonies or psychotherapy Abstract: Psychoactive drugs of fungal origin, psilocin, ibotenic support. As an example, it was experimentally established acid, and muscimol among them have been proposed for recreational that psilocybin, psilocin prodrug of fungal origin, is able to use and popularized since the 1960s, XX century. Despite their well- produce mystical states under favorable circumstances documented neurotoxicity, they reached reputation of being safe and (involving acquired cultural frame of references).10–16 Some nonaddictive. Scientific efforts to find any medical application for details of the study design, particularly the usage of niacin as these hallucinogens in psychiatry, psychotherapy, and even for an active placebo, may suggest that the authors of the first religious rituals support are highly controversial. Even if they show of these experiments known as Good Friday Experiment any healing potential, their usage in psychotherapy is in some cases were aware that religious rituals alone are not neutral for inadequate and may additionally harm seriously suffering patients. mental health.10–28 The states of altered consciousness induced Hallucinogens are thought to reduce cognitive functions. However, by religious settings and facilitated by psychedelic drugs fi in case of indolealkylamines, such as psilocin, some recent ndings increase susceptibility to suggested messages and are not free suggest their ability to improve perception and mental skills, what from negative emotions such as fear, terror, anxiety, shame, would motivate the consumption of “magic mushrooms.” The pres- fi and sense of guilt. Therefore, any religious cult, particularly ent article offers an opportunity to nd out what are the main symp- if combined with psychoactive compounds intake, should toms of intoxication with mushrooms containing psilocybin/psilocin, be considered as being able to alter psychosocial identity. muscimol, and ibotenic acid. The progress in analytical methods Psychotic syndromes evoked in religious purposes are not for detection of them in fungal material, food, and body fluids is fully safe and may induce development of really serious psy- reviewed. Findings on the mechanisms of their biologic activity are chopathologies including confusional syndrome and schizo- summarized. Additionally, therapeutic potential of these fungal psy- phrenia, a disease of at least partly psychosocial etiology.29–35 choactive compounds and health risk associated with their abuse are discussed. It should be pointed out that psilocybin/psilocin, although still scientifically explored as potentially helpful and safe psycho- Key Words: hallucinogens, psilocin, ibotenic acid, muscimol therapy adjunctive,4,10–16,36–40 is presently used to model schizophrenia and to investigate psychosis similar to positive (Ther Drug Monit 2013;35:420–442) symptoms of the disease.41–50 The psychoactive principles of Psilocybe mushrooms, namely psilocybin and psilocin, were isolated and identified INTRODUCTION 51 Psychoactive plants or fungi accompanied religious rituals by Hofmann in 1958. Both these substances, similarly as 1–4 LSD, were originally proposed as incapacitating agents and in many ancient civilizations worldwide. Hallucinogenic com- 7 pounds contained in fungi of Psilocybe and Amanita genera used for intelligence purposes. Ibotenic acid and muscimol seemed to be the most active substances of fly agaric respon- have been used as recreational drugs of abuse since the begin- 52–54 ning of the 1960s, XX century.5,6 Although hallucinogens are sible for its hallucinogenic properties. Exposure to these thought to be safe because of relatively low physiologic tox- substances, especially chronic, not only may constitute a sig- fi icity and dependence potential7,8 nowadays the context of ni cant risk to human mental health but may also induce hallucinogenic compounds consumption, mainly by young other serious disorders including cardiovascular complica- people seeking for unusual experiences, is usually nega- tions and neurodegenerative diseases. Although chemically tive5,6,9 but not exclusively. One exception seems to be the unstable, ibotenic acid should be considered as highly toxic agent if one is aware of convulsant activity and excitotoxicity Received for publication June 19, 2012; accepted January 9, 2013. of its endogenous analogue glutamate. Simultaneously, the From the Department of Analytical and Ecological Chemistry, Opole University, fungal psychedelics of high biologic activity display signifi- Opole, Poland. cant therapeutic potential. Supported by Wroclaw Research Centre EIT+ under the Project “Biotechnologies and advanced medical Technologies”—BioMed (POIG.01.01.02-02-003/08) Hallucinogenic fungi and psychedelics isolated from financed from the European Regional Development Fund (Operational Pro- them are illegal in many countries or their processing and gramme Innovative Economy, 1.1.2). distribution stay under strict regulation.12 However, because The author declares no conflicts of interest. they are easily available from natural habitats, they have Correspondence: Katarzyna Stebelska, PhD, Department of Analytical and Ecological Chemistry, Opole University, Pl Kopernika 11, PL-45-040 become quite popular among growing population of drug Opole, Poland (e-mail: [email protected]). users and are frequent cause of serious poisoning or even – – Copyright © 2013 by Lippincott Williams & Wilkins accidental deaths resulted from their biologic activity.5 9,55 59 420 Ther Drug Monit Volume 35, Number 4, August 2013 Ther Drug Monit Volume 35, Number 4, August 2013 Psilocin, Ibotenic Acid, and Muscimol Therefore, analytical methods elaborated for detection of these when tryptophan is present in the medium from the stage of substances in fungal material and body fluids are also reviewed culture inoculation.75 Replacement of nutrient medium does in this article. not affect psilocybin content.74 Conditions of potassium depletion do not influence considerably mycelium growth but lower psilocybin production.75 Lack of succinate in the Psilocybin/Psilocin as a Secondary Metabolite medium decreases biosynthesis of psilocybin.74 Psilocybin is a secondary metabolite of some species of Psilocybin seems to be present at higher amounts in Agrocybe, Conocybe, Copelandia, Galerina, Gymnopilus, mushroom caps than in the stems.76,77 Psilocybe semilanceata Hypholoma, Inocybe, Panaeolina, Panaeolus, Pholiotina, and P. serbica var. bohemica (synonymous with P. bohemica) Pluteus, and Psilocybe genera.60–63 The major part of the were found to contain high amounts of psilocybin up to 1% of known psychoactive species belongs to the genus Psilocybe. dry weight. Psilocybe cubensis seemed to contain minor They are saprotrophic on wood, dung, moss, soil, and litter. amounts of psilocybin and low amounts of psilocin (0.63% Psilocybe cyanescens, P. serbica var. bohemica, P. serbica and 0.11%, respectively). The contents of psilocybin and psi- var. arcana, and P. semilanceata are probably the only spe- locin in the sample of P. cyanescens were 0.32% and 0.51%, cies containing sufficient for intoxication amounts of psilocin/ respectively.78 Psilocybe serbica var. bohemica collected in psilocybin that can grow in natural or near natural habitats in Europe were found to contain minor amounts of psilocybin the Middle and North Europe.60,64–66 Psilocybe cubensis is the (content between 0.33% and 0.62%) and almost no psilocin. most popular natural source of psilocybin in the warmer Psilocybe cyanescens from the Pacific Northwest, United regions of the Americas. In the United States, it can be found States, contained both psilocybin (0.41%–0.98%) and psilocin in the wild throughout the southeast to Texas and the Pacific (0.23%–0.93%).79 Northwest. The fungus is common in Mexico and other Cen- During mycelium development, some processes are tral American countries, and it is also known from South controlled by light or are light responsive,80 and psilocybin American, Asian, Australian and Oceanian localities.62,67,68 biosynthesis is also somehow under control of ultraviolet Psilocybe subaeruginosa occurs commonly in Australia and (UV) radiation. Psilocybe genus mushrooms produce fruit is widespread in New Zealand and Tasmania.68,69 bodies after UV or blue light irradiation.81 The caps of fruit Season-dependent availability of psilocybin-containing bodies formed from poorly enlightened cultures develop blu- mushrooms has stimulated the search for methods to cultivate ish phototropic zone originating from oxidation products of these fungi. Culturing of the mushrooms became common indole compounds. It is also thought that the highest level of after reports on the methodology seemed in both scientific psilocybin coincides with sporulation time. literature and specialist books. It seems that most recreation- ally used mushrooms are cultivated rather than picked wild at Analytical Methods Used for present. For illicit home growers, P. cubensis and its varieties Psilocybin/Psilocin Detection and Isolation are generally the mushrooms of choice because they are easy to culture and fruit readily in vitro, producing a significant Methods of Extraction amount of biomass with each flush.60,67 Psilocybin due to the presence of highly polar phos- Alkaloids isolated from hallucinogenic mushrooms phate group is well soluble in water
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