Send Orders for Reprints to [email protected] 26 Current Neuropharmacology, 2015, 13, 26-46 Recreational Use, Analysis and Toxicity of Tryptamines Roberta Tittarelli1, Giulio Mannocchi1, Flaminia Pantano1 and Francesco Saverio Romolo1,2,* 1Legal Medicine Section, Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, “Sapienza” University of Rome, Viale Regina Elena, 336, 00161 Rome, Italy; 2Institut de Police Scientifique, Université de Lausanne, Batochime, 1015 Lausanne, Switzerland Abstract: The definition New psychoactive substances (NPS) refers to emerging drugs whose chemical structures are similar to other psychoactive compounds but not identical, representing a “legal” alternative to internationally controlled drugs. There are many categories of NPS, such as synthetic cannabinoids, synthetic cathinones, phenylethylamines, piperazines, ketamine derivatives and tryptamines. Tryptamines are naturally occurring compounds, which can derive from the amino acid tryptophan by several biosynthetic pathways: their structure is a combination of a benzene ring Roberta Tittarelli and a pyrrole ring, with the addition of a 2-carbon side chain. Tryptamines include serotonin and melatonin as well as other compounds known for their hallucinogenic properties, such as psilocybin in ‘Magic mushrooms’ and dimethyltryptamine (DMT) in Ayahuasca brews. Aim: To review the scientific literature regarding tryptamines and their derivatives, providing a summary of all the available information about the structure of these compounds, their effects in relationship with the routes of administration, their pharmacology and toxicity, including articles reporting cases of death related to intake of these substances. Methods: A comprehensive review of the published scientific literature was performed, using also non peer-reviewed information sources, such as books, government publications and drug user web fora. Conclusions: Information from Internet and from published scientific literature, organized in the way we proposed in this review, provides an effective tool for specialists facing the emerging NPS threat to public health and public security, including the personnel working in Emergency Department. Keywords: Clinical effects, Emergency Departments, Fatalities, Forensic Toxicology, Intoxication, New Psychoactive Substances (NPS), Tryptamines. INTRODUCTION regards the Internet “as a growing source of on-line drug trafficking”: products purchased on Internet may vary over The New psychoactive substances (NPS) are defined by time proposing chemicals always different, not listed in European Community (2005) as “substances of abuse either literature, meaning that users are often unaware of what or in a pure form or preparation that are not controlled by the 1961 Single Convention on Narcotics Drugs or the 1971 how much they are taking [4], causing increasing risks to Convention on Psychotropic Substances, but which may public health. The phenomenon of marketing illicit drug pose a public health threat comparable to scheduled ‘‘derivatives’’ grew mainly because of their easy availability substances” [1]. According to Zuba, “they are created on the Internet or in “head shops”. The use of NPS has usually by manipulating already existing psychoactive increased dramatically in recent years: only in the European substances or, less, by finding drugs with a new chemical Union, the number of NPS identified has risen “from 14 at structure that may produce similar effects to those of the the end of 2005 to 236 by the end of 2012” [5]. The majority of illegal drugs of abuse” [2]. They may be formulated as new recreational synthetic drugs fall into one of the following “bulk powders, liquids, tablets, capsules, blotters,” or herbal psychoactive drug categories: synthetic cannabinoids, synthetic preparations, indeed on the web sites these drugs are sold as cathinones, phenylethylamines, piperazines, ketamine “research chemicals,” “incense,” “bath salts,” or “plant- derivatives and tryptamines. growth fertilizers,” equipped with labels specifying that the Tryptamines are a group of monoamine alkaloids (Fig. 1), products are “not for human consumption” or “not for sale to which can be synthesized by decarboxylation of the minors” [3]. The International Narcotics Control Board aminoacid tryptophan: they can be found in plants, fungi, animals, microbes and amphibia [6]. *Address correspondence to this author at the Legal Medicine Section, Tryptamines have an indole ring structure, a fused double Department of Anatomical, Histological, Forensic Medicine and Orthopedic ring comprising of a pyrrole ring and a benzene ring, joined Sciences, “Sapienza” University of Rome, Viale Regina Elena, 336, 00161 Rome, Italy; Tel: 00390649912581; Fax: 00390649912614; to an amino group by 2 carbon side chain. E-mail: [email protected] 1570-159X/15 $58.00+.00 ©2015 Bentham Science Publishers Recreational Use, Analysis and Toxicity of Tryptamines Current Neuropharmacology, 2015, Vol. 13, No. 1 27 Fig. (1). Tryptamine structure. The tryptamines play a fundamental role in human life: serotonin (5-hydroxytryptamine, 5-HT), one of the most important signaling hormones [7] in the body, is a tryptamine natural derivative involved in regulation and modulation of multiple processes within the central nervous system, such as sleep, cognition, memory, temperature regulation and behavior [8]. Moreover, mammalian brain contains very low concentrations (in the low ng/g range) of tryptamine, which may act as a neurotransmitter or modulator Fig. (3). Tryptamine structure as template for new psychoactive [9]: it acts as a serotonin releasing agent and it is an enhancer compounds. of serotonergic activity [10]. Gibbons in his publication, defines the nature “an astounding chemist (..) able to produce α-methyltryptamine (5-MeO-AMT)], being the presence of compounds that have profound effects on the central nervous an alpha carbon methyl group, a characteristic in common system (CNS)”[11]. Naturally occurring derivatives of the with amphetamine [14, 18]. The synthesis and the effects of tryptamines are present in the ‘Magic mushrooms’ belonging to Psilocybe cubensis species, which contain psilocybin these compounds have been fully investigated by Alexander T. Shulgin who described his experiences within the book (4-phosphoryloxy-N,N-dimethyltryptamine) and psilocin Tihkal [19]: he identified 55 molecules and he tested these (4-hydroxy-N,N-dimethyltryptamine), the latter showing substances on volunteers to assess their effects according to marked similarities with serotonin (Fig. 2). his rating scale. Recreational use of tryptamines requires Another example of the ability of the natural world to only minute amounts to produce psychotropic phenomena create hallucinogenic substances, is the 5-hydroxy-N,N- and has been associated to intoxications and fatalities for dimethyltryptamine (bufotenine), a positional isomer of several reasons, including low toxic concentrations. Moreover, psilocin [12], which is contained in the skin and glands of these molecules are not routinary detected with common various species of toad of the genus Bufo [13]. Chemical screening panels, so far in emergency rooms the test could modifications of the nucleus structure of the tryptamine result completely negative leading to misunderstanding molecule produce new compounds which may cause diagnosis or therapy and limited evaluation of the phenomenon. alterations of the physical and mental status: substitutions on It is very important to organize the information pertaining to the indole ring, on the two carbons of the side chain and these substances to provide a tool for specialists facing this alkylation of the side-chain nitrogen result in new emerging threat to public health and public security. For this neuroactive compounds, ranging from toxic substances to reason a comprehensive review of the scientific literature anti-migraine drugs, such as Sumatriptan [14], Rizatriptan and internet sites regarding tryptamines and their derivatives and Zolmitriptan (Fig. 3). was carried out, providing a summary of all the available information about the structure of these compounds, their Tryptamines show agonist action at multiple receptors, effects in relationship with the routes of administration including 5HT2a-1a-2c [15] serotonin receptors [16], and and their toxicity, including articles reporting cases of several ion channels [17]. In general, tryptamines seem to death related to intake of these substances and analytical have hallucinogenic properties, rather than stimulant or methods for the determination and quantification of some entactogenic characteristics: their alpha methylation leads to tryptamines. stimulant activity [α-methyltryptamine (AMT), 5-methoxy- CLASSIFICATION OF TRYPTAMINES BASED ON THEIR CHEMICAL STRUCTURES Several classifications have been suggested for these substances. Nichols classified tryptamines in two main groups: -the simple tryptamines, including dimethyltryptamine (DMT), and the ergolines (a group of chemical compounds that were originally synthesized from a fungus ergot, among which is the lysergic acid diethylamide (LSD). Fantegrossi divided tryptamines in three subgroups: (1) simple tryptamines, without modification of the indole ring; (2) tryptamines having a modification on the 4-position on the indole ring; Fig. (2). Psilocin and serotonin structure. (3) tryptamines having a modification on the 5-position. Only 28 Current Neuropharmacology,