Profiling psychoactive tryptamine-drug synthesis by focusing on detection using mass spectrometry

Abstract

The tryptamine nucleus is a building block for many biologically-active derivatives (e.g., neurotransmitter serotonin or antimigraine drugs of the triptan series). A variety of N,N-dialkylation of the nitrogen side chain can result in derivatives with psychoactive and hallucinogenic properties that are accessible by a large number of synthetic procedures.

The renewed interest in human clinical studies coincides with increased public interest and exchange of information on the Internet, including discussion in scientific, popular and clandestine literature. Over the past few years, an increasing number of case reports have attracted the attention of clinical, pharmaceutical, forensic and public-health communities, underlining the current lack of pharmaco-toxicological and analytical data.

This review assesses the current state of knowledge about the analytical profiling of drugs and by-products obtained from synthetic procedures discussed on Internet websites and scientific literature. Due to space considerations, we focus on detection using mass spectrometry (MS). We discuss commonalities and differences when considering fragmentation under a variety of ionization conditions and mass analysis using single-stage and multi-stage modes of MS.

Key features of mass-spectral fragmentation include formation of iminium-ion C_nH_2n+2N⁺, normally assumed to be represented by appropriately substituted CH₂N⁺(R¹R²) species. Isomeric derivatives can often be differentiated by secondary and tertiary fragmentations that form C_nH_2n+2N⁺ species after loss of neutrals. Soft-ionization techniques (e.g., electrospray) are often characterized by intense [3-vinylindole]⁺-type species that reflect the extent of substitution on the indole ring. The fact that some tryptamines were found sensitive to halogenated solvents reminds the analyst to be aware of the potential for misinterpreting data when investigating the presence of route-specific impurities.

Introduction

The ability of humans to experience a wide range of altered states of consciousness has always been the subject of study throughout history. Alterations from what may be called a “normal” waking state may be induced by drugs and other non-drug-facilitated methods or may occur naturally [1]. As a consequence, the study of the human mind satisfies a range of diverse needs across the disciplines. One of the key molecules involved in regulation and modulation of fundamental processes within the central nervous system is neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) 1 (Fig. 1). This simple derivative is involved in a variety of functions (e.g., appetite, sex, sleep, cognition and memory, sensory perception, mood, nociception, endocrine function, temperature regulation, motor activity and behavior) [2]. It is therefore not surprising that chemical modifications of the tryptamine nucleus result in the availability of a plethora of bioactive and neuroactive compounds ranging from highly toxic materials to medicinally important products.

N,N-dialkylation of the primary amine function of the tryptamine building block results in a large number of derivatives with psychoactive and/or hallucinogenic properties, and the impact on mood, cognition and perception appears to vary depending on the nature of substituents. Fig. 1 shows a generalized tryptamine structure, where psychoactivity is greatly affected by substitution on the 4 and 5 positions of the indole ring, the side-chain carbon and alkylation of the side-chain nitrogen [3]. Most of the psychoactive N,N-disubstituted derivatives known may show oral activity, but homologation of the N,N-dialkyl substituents appears to attenuate potency [4], [5]. A number of naturally-occurring psychoactive tryptamines are N,N-dimethylated representatives: N,N-dimethyltryptamine (DMT) 2, psilocybin 3, psilocin 4 (4-OH-DMT), and 5-methoxy- and 5-hydroxy-DMT (bufotenin) (5 and 6, respectively). Psilocybin can be found in many mushroom species [6], [7] whereas the remaining derivatives are found in many plants [8], [9]. The pharmacology of these derivatives is complex but current knowledge points towards the involvement of 5-HT_{1A & 2A} receptor sub-types [10], [11], [12]. Recent findings also suggested that DMT 2 serves as an agonist at the sigma-1 receptor [13] and that a number of N,N-dialkylated tryptamines were found to be substrates at the plasma membrane serotonin transporter and the vesicle monoamine transporter [14].

As far as human clinical studies are concerned, only DMT 2 and psilocybin 3 have been extensively studied in recent years (e.g., [15], [16], [17], [18], [19], [20] and references therein). So far, only the N,N-dimethylated tryptamines are known to be present in nature and the term “designer tryptamines” is often used when referring to synthetically-accessible analogues, since many of the N,N-dialkylated tryptamines are prohibited by legislation. A corollary is the inability to exercise quality control over compounds prepared illegally, often leading to low-quality drugs with unpredictable biological activity and ill-defined impurity profiles.

From a molecular point of view, differentiation between legal and illegal compounds is not always straightforward if one considers, for example, that the so-called triptan-type antimigraine drugs (e.g., Sumatriptan 7) are derivatives of DMT 2 substituted on the 5-position (Fig. 1). Interestingly, 5,6-dibromo-DMT 8 and 5-bromo-DMT 9 have been recently isolated from three marine sponges found in Florida, USA, where 5,6-dibromo-DMT 8 appeared to show antidepressant-like activities in rodents, whereas the 5-bromo-DMT 9 displayed potential sedative properties in the chick anxiety-depression model [21].

The renewed interest in exploring tryptamine-based hallucinogens within the clinical context and the availability of scientific and popular literature on Internet websites coincides with increased popularity within recreational communities. Most of the currently-known data on the psychoactive effects of higher N,N-dialkylated tryptamines are based on self experimentation and little is known about their pharmaco-toxicological properties, particularly with long-term use [4], [5]. Dedicated websites such as Erowid (www.erowid.org) host a wide range of useful information relating to every aspect of consumption of legal and illegal drugs. It provides a platform for existing users and those contemplating use. 5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) 10 is one of the few tryptamine representatives that was subject to case reports and that has been implicated in toxic and fatal responses (e.g., [22], [23], [24]), so leading to increased public attention.

Compared with the vast amount of literature available on the analytical characterization and profiling of phenethylamine and amphetamine-type drugs, relatively little has been published in the area of psychoactive tryptamines. However, as mentioned above, the increasing interest in the so-called designer tryptamines has moved this area more into the spotlight of clinical, forensic and public-health-based investigations. In this review, we aim to provide an account of the key literature published on the characterization of synthetic routes obtained from Internet websites and research literature.