Tryptamines are a group of monoamine alkaloids, which can be synthesized by decarboxylation of the aminoacid tryptophan: they can be found in plants, fungi, animals, microbes and amphibia. Tryptamines have an indole ring structure, a fused double ring comprising of a pyrrole ring and a benzene ring, joined to an amino group by 2 carbon side chain.

Synthesis of Tryptamine

Add 500 mL of tetrahydrofuran to a 1000 mL single-necked flask, and add 11.4 g (300 mmol) of lithium aluminum hydride and 9.4 g (50 mmol) of (E)-3-(nitrovinyl) indole. Heat and reflux them for 7 h. Use water to quench lithium aluminum hydride not fully reacted. Conduct suction filtration, remove the solvent in the filtrate and add ethyl acetate and water to separate liquid. Wash the organic phase with a saturated saline solution, dry it with anhydrous sodium sulfate, remove solvent to obtain a red viscous substance, and dry it naturally to obtain 8.9 g of brown solid. The yield is 89% and the melting point is 115-117° C.; (0100) 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H, NH), 7.62 (d, 3JHH=7.6 Hz, 1H, Ar-H), 7.36 (d, 3JHH=8.0 Hz, 1H, Ar-H), 7.20 (t, 3JHH=7.6 Hz, 1H, Ar-H), 7.12 (t, 3JHH=7.3 Hz, 1H, Ar-H), 7.02 (s, 1H, Ar-H), 3.04 (t, 3JHH=6.4 Hz, 2H, CH2), 2.91 (t, 3JHH=6.8 Hz, 2H, CH2), 1.47 (s, 2H, NH2)[1]

The Effects of Tryptamine Psychedelics in the Brain

There is an increasing interest in the neural effects of psychoactive drugs, in particular tryptamine psychedelics, which has been incremented by the proposal that they have potential therapeutic benefits, based on their molecular mimicry of serotonin. It is widely believed that they act mainly through 5HT2A receptors but their effects on neural activation of distinct brain systems are not fully understood. In sum, the available evidence points towards strong neuromodulatory effects of tryptamine psychedelics in key brain regions involved in mental imagery, theory of mind and affective regulation, pointing to potential therapeutic applications of this class of substances.[2]

This concept that neural effects stem mainly from 5-HT2AR has been challenged for indoleamine/tryptamine hallucinogens. A large body of evidence demonstrates indeed that both 5-HT1A and 5-HT2A receptors are responsible for the behavioral effects of these hallucinogens (Halberstadt and Geyer, 2011). These authors point out that, in general, different neurotransmitter systems contribute to the effects of indoleamine/tryptamine hallucinogens, which in the case of LSD involves also dopamine receptors. In sum, the available evidence points towards strong neuromodulatory effects of tryptamine psychedelics in key brain regions involved in mental imagery, theory of mind and affective regulation, pointing to potential therapeutic applications of this class of substances.

Recreational Use, Analysis and Toxicity of Tryptamines

The tryptamines play a fundamental role in human life: serotonin (5-hydroxytryptamine, 5-HT), one of the most important signaling hormones 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. Moreover, mammalian brain contains very low concentrations (in the low ng/g range) of tryptamine, which may act as a neurotransmitter or modulator: it acts as a serotonin releasing agent and it is an enhancer of serotonergic activity. Gibbons in his publication, defines the nature “an astounding chemist (..) able to produce compounds that have profound effects on the central nervous system (CNS)”. Naturally occurring derivatives of the tryptamines are present in the ‘Magic mushrooms’ belonging to Psilocybe cubensis species, which contain psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and psilocin (4-hydroxy-N,N-dimethyltryptamine), the latter showing marked similarities with serotonin.[3]

The information regarding the effects of tryptamines reported in this paragraph, is collected from websites, so these effects are exclusively the result of personal experiences of authors and do not follow the use of the scientific method. They are reported because Internet is probably one of the most effective sources of timely information for any specialist or organization interested in the subject. The tryptamines users are not always aware of what they have purchased and of its chemical constituents, and there are many risks associated with the possibility of overdose, repeated administration and incorrect route of administration. In this section, we are going to report the main effects connected with the use of tryptamines, included the one reported as “positive” by authors. The routes of administration of the various tryptamines are one of the key factors that need to be evaluated: some can be taken orally or intramuscularly or intravenously, or can be smoked or inhaled, showing an increased of hallucinogenic sensations, especially in relation to dose and repeated-dose toxicity due to a delayed onset of phenomenology.

Another case of fatal intoxication with AET is reported by Daldrup. After ingestion of α-ethyltryptamine a young man developed agitation, hyperpyrexia: he showed effects similar to those known from intoxication with amphetamines, MAO inhibitors, and thymoleptics. The exact amount of α-ethyltryptamine taken are not known, but it could have been in the range of 700 mg. The level in postmortem blood was 1.1 mg/l. Malignant hyperthermia is discussed as a possible cause of death. Tryptamines are not routinary detected with common immunoassay-based techniques, leading, for example, to misunderstanding in diagnosis or therapy in Emergency Departments, as toxicological screening tests could result completely negative. Many psychoactive substances belong to the chemical class of tryptamines. There are old compounds known for their hallucinogenic properties, such as psilocybin in ‘Magic mushrooms’ and dimethyltryptamine (DMT) in Ayahuasca brews, and there are several New psychoactive substances (NPS), emerging drugs whose chemical structures are similar to other psychoactive compounds but not identical, so that they represent a “l(fā)egal” alternative to internationally controlled drugs.

The evolution in the use of tryptamines

The most common hallucinogenic fungi containing tryptamine derivatives are the Psilocybe spp. mushrooms, which are widely distributed around the world, being extremely used by indigenous people for centuries in sacred rituals, especially in South American countries (particularly in Colombia), Mexico, India, Japan, New Guinea and Australia. Studies on the chemical composition of the psychoactive mushrooms have focused on the two main hallucinogenic compounds, namely psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and psilocin (4-hydroxy-N,N-dimethyltryptamine), which are thermostable, not being inactivated by preparations involving temperature cycles. These naturally occurring tryptamines were isolated for the first time in 1958.[4]

Another known natural tryptamine is bufotenine or 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT), an N-alkylated derivative of serotonin and also a structural isomer of psilocin (Chamakura 1994). During World War I, Handovsky (1920) isolated bufotenine, while in 1934 Wieland (Wieland et al. 1934) established its chemical structure and in 1935 Hoshino (Hoshino and Shimodaira 1935) synthesized it for the first time. Bufotenine and its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) are the main psychoactive ingredients of the secretion of the American desert toad, Bufo alvarius, and have been used in the production of hallucinogenic snuff in South America. As with other tryptamines previously described, the bufotenine appears in many hallucinogenic plants. Noteworthy, several methylated tryptamines have been detected as endogenous compounds in humans too, though their biological roles are still unclear. 5-MeO-DMT can be synthesized in human pineal gland and has been detected in both pineal gland and urine. The methylated indolamines are also present in retina at relatively high levels (Leino and Airaksinen 1985). Bufotenine itself can have endogenous origin too (Barker et al. 2012) since 5-MeO-DMT is oxidatively demethylated to bufotenine in the human body (Shen et al. 2010). Although hallucinogens are generally considered to be physiologically safe molecules, reports of intoxication and deaths related to the use of recreational tryptamines have been described over the last years. Therefore, more research on their pharmacological and toxicological properties is fully required in order to access the actual potential hazard of synthetic tryptamines.

References

[1]NANKAI UNIVERSITY - US2016/326166, 2016, A1

[2]Castelhano J, Lima G, Teixeira M, Soares C, Pais M, Castelo-Branco M. The Effects of Tryptamine Psychedelics in the Brain: A meta-Analysis of Functional and Review of Molecular Imaging Studies. Front Pharmacol. 2021 Sep 29;12:739053.

[3]Tittarelli R, Mannocchi G, Pantano F, Romolo FS. Recreational use, analysis and toxicity of tryptamines. Curr Neuropharmacol. 2015 Jan;13(1):26-46.

[4]Araújo AM, Carvalho F, Bastos Mde L, Guedes de Pinho P, Carvalho M. The hallucinogenic world of tryptamines: an updated review. Arch Toxicol. 2015 Aug;89(8):1151-73.