RE104: Synthesis and Activity of a Novel Serotonergic Psychedelic Prodrug of 4-Hydroxy-N,N-diisopropyltryptamine.

Results from randomized clinical trials of psilocybin in depressive disorders highlight the therapeutic potential of serotonergic psychedelic compounds in mental health disorders. The synthetic 5-hydroxytryptamine 2A receptor agonist 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT) is structurally similar to psilocin but is reported to have a shorter duration (2-3 h) of psychedelic effects, suggesting the potential for psilocybin-like therapeutic activity with reduced clinical resource burden. Here, we describe the preclinical and translational characterization of RE104, a 4-OH-DiPT prodrug comprising a glutarate moiety designed to cleave rapidly in situ and thus provide reasonable bioavailability of the active drug. Plasma concentration of 4-HO-DiPT over time in PK experiments in rats was correlated with head-twitch intensity. The half-life of 4-OH-DiPT was 40 min after subcutaneous administration of RE104 in rats. In a forced swim test, a single dose of RE104 (1 mg/kg) significantly reduced mean immobility time at 1 week compared with vehicle (P < 0.001), confirming translational antidepressant potential. Taken together, these data with RE104 show that the glutarate ester can act as an efficient prodrug strategy for 4-HO-DiPT, a unique short-duration psychedelic with potential in depressive disorders.

Chemoenzymatic Synthesis of 5-Methylpsilocybin: A Tryptamine with Potential Psychedelic Activity.

A novel analogue of psilocybin was produced by hybrid chemoenzymatic synthesis in sufficient quantity to enable bioassay. Utilizing purified 4-hydroxytryptamine kinase from Psilocybe cubensis, chemically synthesized 5-methylpsilocin (2) was enzymatically phosphorylated to provide 5-methylpsilocybin (1). The zwitterionic product was isolated from the enzymatic step with high purity utilizing a solvent-antisolvent precipitation approach. Subsequently, 1 was tested for psychedelic-like activity using the mouse head-twitch response assay, which indicated activity that was more potent than the psychedelic dimethyltryptamine, but less potent than that of psilocybin.

Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids.

While the use of ergot alkaloids in folk medicine has been practiced for millennia, systematic investigations on their therapeutic potential began about 100 years ago. Subsequently, Albert Hofmann's discovery of lysergic acid diethylamide (LSD) and its intense psychedelic properties garnered worldwide attention and prompted further studies of this compound class. As a result, several natural ergot alkaloids were discovered and unnatural analogs were synthesized, and some were used to treat an array of maladies, including Alzheimer's and Parkinson's disease. While LSD was never commercially approved, recent clinical studies have found it can be an innovative and effective treatment option for several psychiatric disorders. Ongoing biosynthetic and total synthetic investigations aim to understand the natural origins of ergot alkaloids, help develop facile means to produce these natural products and enable their continued use as medicinal chemistry lead structures. This review recounts major developments over the past 20 years in biosynthetic, total synthetic, and pharmaceutical studies. Many ergot alkaloid biosynthetic pathways have been elucidated, with some of them subsequently applied toward "green" syntheses. New chemical methodologies have fostered a fast and efficient access to the ergoline scaffold, prompting some groups to investigate biological properties of natural product-like ergot alkaloids. Limited pharmaceutical applications have yet to completely bypass the undesirable side effects of ergotism, suggesting further studies of this drug class are likely needed and will potentially harness major therapeutic significance.

A 4-Year Retrospective Analysis of Patients Presenting at the Emergency Department With Synthetic Cannabinoid Intoxication in Turkey.

PURPOSE/BACKGROUND: The number of patients with acute synthetic cannabinoid intoxication (SCI) has increased in recent years although the prohibition of its legal sale and use in Turkey despite other countries allowing to some extent sale and use. The reported clinical findings of acute SCI are similar to the symptoms of several diseases. The first case of acute SCI seen in our hospital was in 2014. The aim of this study was to share the data of synthetic cannabinoid use in a research hospital in Turkey and to contribute the epidemiologic data globally betwen 2014 and 2017. METHODS/PROCEDURES: A retrospective evaluation was made of patients who presented at emergency department (ED) because of SCI between January 2014 and December 2017. The initial diagnosis of the patients was done either via their self-report or clinician's clinical observation (family history with hallucination, lethargy, convulsions, dizziness, etc.). Totally, 352 patients were included to the study whose cannabioid use was proven with their urine drug analysis. FINDINGS/RESULTS: Men were predominantly high (93.8%). Nearly all patients (93.5%) were followed up and discharged in 24 hours. Among them, 21 (5.9%) patients were admitted for hospitalization, and mortality was seen in 2 (0.6%). The mean number of previous presentations at ED with a similar diagnosis was 8.6 ± 10.31. IMPLICATIONS/CONCLUSIONS: Great care must be taken in respect of complications related to SCI, which can even result in death. Patients have a tendency to not disclose the substance they have taken because it is illegal. Patients presenting at ED with recurrent symptoms must be referred to relevant legal authorities. For patients presenting with different clinical effects, SCI must be considered.

Synthesis and characterization of high-purity N,N-dimethyltryptamine hemifumarate for human clinical trials.

Since 2006, there has been a resurgent interest in the pharmacology and therapeutics of psychedelic drugs. Psilocybin, the 4-phosphoryl ester of N,N-dimethyltryptamine (DMT), has been studied most often, but DMT itself is also appealing because of its brief but profound psychological effects and its presence as an endogenous substance in mammalian brain. Although there have been a few studies of ayahuasca, a DMT-containing water infusion, only one human study with pure DMT has been reported since the early 2000s. Newly planned clinical trials to assess the safety and efficacy of DMT in humans with major depressive disorders require high-purity water-soluble DMT for intravenous administration. Accordingly, we synthesized and characterized DMT hemifumarate for these upcoming studies. The synthetic approach of Speeter and Anthony was slightly modified to gain some efficiency in time. In particular, this is the first known report to use aluminum hydride, generated in situ from lithium aluminum hydride, to reduce the intermediate 2-(1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide to DMT. A quench protocol was developed to produce a good yield of exceptionally pure free base DMT upon workup, which was then converted to the hemifumarate salt. Analysis of the final product included differential scanning calorimetry, thermogravimetric analysis, gas chromatography-mass spectrometry (GC-MS), 1 H and 13 C nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, residual solvent analysis by GC headspace sampling, X-ray powder diffraction analysis, and residual lithium analysis by inductively coupled plasma-mass spectrometry. The DMT hemifumarate was minimally 99.9% pure, with no significant impurities or residual solvents, thus meeting regulatory standards for administration to humans.

Synthesis and determination of analytical characteristics and differentiation of positional isomers in the series of N-(2-methoxybenzyl)-2-(dimethoxyphenyl)ethanamine using chromatography-mass spectrometry.

N-(2-Methoxybenzyl)-2,5-dimethoxyphenethylamines (NBOMes) are synthetic phenethylamine derivatives emerging on the global drug market and reported to be associated with untoward effects in people who use drugs. Its action involves agonism at serotonin 5-HT2A receptors, affecting cognitive and behavioral processes. However, certain isomers of NBOMes may not show any psychoactive effects. They are not controlled by legislation and can be tested as pharmaceutical drugs. This study deals with the differentiation among positional isomers of 25H-NBOMe differing in the position of the two methoxy groups in the phenylethyl moiety of the molecule, using chromatography-mass spectrometry methods. The gas chromatography analysis showed that the isothermal mode was more efficient than the usually applied temperature-programming mode for the separation of the mentioned isomers. Electron ionization mass spectra of 25H-NBOMe isomers were highly similar, often resulting in a high probability of erroneous identification. However, mass spectra of their trifluoroacetyl or pentafluoropropanoyl derivatives were easily identified as they contained fragments with many significant differences. The proposed analysis using liquid chromatography-tandem mass spectrometry could distinguish the isomers of 25H-NBOMe without the need for any derivatization.

The selective 5-HT2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [3H]25CN-NBOH.

The remarkable effects exhibited by classical psychedelics in recent clinical trials have spawned considerable interest in 5-HT2A receptor (5-HT2AR) activation as a treatment strategy for several psychiatric/cognitive disorders. In this study we have continued our development of 25CN-NBOH, one of the most 5-HT2AR-selective agonists reported to date, as a pharmacological tool for exploration of 5-HT2AR expression and functions. The importance of the 2' and 3' positions in 25CN-NBOH as structural hotspots for its 5-HT2AR activity was investigated by synthesis and pharmacological characterization of six novel analogs at 5-HT2AR and 5-HT2CR in binding and functional assays. While the 5-HT2AR activity of 25CN-NBOH was retained in 3'-methyl, 2',3'-chroman, 2',3'-dihydrofuran and 2',3'-furan analogs, the 3'-methoxy and 3'-ethyl analogs displayed substantially lower binding affinities and agonist potencies than 25CN-NBOH. Interestingly, the 2',3'-substitution pattern was also a key determinant of agonist efficacy, as all six analogs exhibited low-efficacy partial agonism or de facto antagonism at the 5-HT2AR in the functional assays. Systemic administration of 25CN-NBOH and its close structural analog 25CN-NBMD induced robust head-twitch response in mice, a well-established behavioural effect of 5-HT2AR activation in vivo, and 25CN-NBOH mediated robust reductions in the activity of mice in an anxiety-related marble burying assay, which supports the proposed beneficial effects of 5-HT2AR activation on disorders characterized by cognitive rigidity. Finally, tritiated 25CN-NBOH exhibited high 5-HT2AR binding affinity (KD ~1 nM) and selectivity against 5-HT2BR and 5-HT2CR in equilibrium and kinetic binding studies of the recombinant receptors, and in concordance [3H]25CN-NBOH displayed substantial specific, ketanserin-sensitive binding to cortex and small levels of binding to choroid plexus in rat brain slices in autoradiography studies. In conclusion, this work delineates the subtle molecular determinants of the 5-HT2AR activity in 25CN-NBOH, substantiates the potential in this compound and its analogs as tools for in vivo studies of the 5-HT2AR, and introduces a novel selective agonist radioligand as another potentially valuable tool for future explorations of this receptor.

Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship Studies.

Ketamine, N,N-dimethyltryptamine (DMT), and other psychoplastogens possess enormous potential as neurotherapeutics due to their ability to potently promote neuronal growth. Here, we report the first-ever structure-activity relationship study with the explicit goal of identifying novel psychoplastogens. We have discovered several key features of the psychoplastogenic pharmacophore and used this information to develop N,N-dimethylaminoisotryptamine (isoDMT) psychoplastogens that are easier to synthesize, have improved physicochemical properties, and possess reduced hallucinogenic potential as compared to their DMT counterparts.

Psychosis and synthetic cannabinoids.

Synthetic cannabinoid (SC) products have gained popularity as abused drugs over the past decade in many countries. The SCs broadly impact psychological state (e.g., mood, suicidal thoughts and psychosis) and physiological functions (e.g., cardiovascular, gastrointestinal and urinary). This review is about the effects of SCs on psychotic symptoms in clinical settings and the potentially relevant chemistry and mechanisms of action for SCs. Induction of psychotic symptoms after consuming SC products were reported, including new-onset psychosis and psychotic relapses. The role of SCs in psychosis is more complex than any single chemical component might explain, and these effects may not be a simple extension of the typical effects of cannabis or natural cannabinoids.

Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD).

Lysergic acid diethylamide (LSD) is one of the most potent psychoactive agents known, producing dramatic alterations of consciousness after submilligram (≥20 µg) oral doses. Following the accidental discovery of its potent psychoactive effects in 1943, it was supplied by Sandoz Laboratories as an experimental drug that might be useful as an adjunct for psychotherapy, or to give psychiatrists insight into the mental processes in their patients. The finding of serotonin in the mammalian brain in 1953, and its structural resemblance to LSD, quickly led to ideas that serotonin in the brain might be involved in mental disorders, initiating rapid research interest in the neurochemistry of serotonin. LSD proved to be physiologically very safe and nonaddictive, with a very low incidence of adverse events when used in controlled experiments. Widely hailed by psychiatry as a breakthrough in the 1950s and early 1960s, clinical research with LSD ended by about 1970, when it was formally placed into Schedule 1 of the Controlled Substances Act of 1970 following its growing popularity as a recreational drug. Within the past 5 years, clinical research with LSD has begun in Europe, but there has been none in the United States. LSD is proving to be a powerful tool to help understand brain dynamics when combined with modern brain imaging methods. It remains to be seen whether therapeutic value for LSD can be confirmed in controlled clinical trials, but promising results have been obtained in small pilot trials of depression, anxiety, and addictions using psilocybin, a related psychedelic molecule.

The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production.

Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.

Toxicokinetics of the Synthetic Cathinone α-Pyrrolidinohexanophenone.

Synthetic cathinones inhibit monoamine transporters, such as serotonin, norepinephrine, and dopamine transporters, and act on the central nervous system via increasing synaptic concentrations of monoamines. These compounds, which are highly addictive and potentially poisonous, are new psychoactive substances. In this study, we investigated the toxicokinetics of the synthetic cathinone, α-pyrrolidinohexanophenone (α-PHP), and assessed the relationship between the toxicokinetics and the long-term clinical symptoms induced by α-PHP in a male patient. The patient (39 years old) suddenly started uttering inarticulate words and demonstrating incomprehensible behavior in his house, and was brought to the emergency department of Iwate Medical University hospital. He presented with psychotic symptoms, such as hallucinations and delusion; however, his vital signs were normal. The hallucinations and delusion improved by the third day of hospitalization. Toxicological analysis was performed using liquid chromatography-tandem mass spectrometry with QuEChERS extraction. α-PHP was detected in his serum at a concentration of 175 ng/mL on his arrival at the hospital. His serum concentrations of α-PHP were serially determined and their natural logarithms were plotted against time after arrival. Although serum concentrations at early time points were lacking, the obtained curve was consistent with a two-compartment model and indicated a serum elimination half-life of 37 h. The long-lasting psychotic symptoms induced by synthetic cathinones appear to be correlated with their toxicokinetic characteristics, such as their long half-lives. Finally, interpreting the toxicokinetics of synthetic cathinones may provide useful information for the toxicological assessment of new psychoactive substances for forensic and clinical purposes.

The synthesis and characterisation of MDMA derived from a catalytic oxidation of material isolated from black pepper reveals potential route specific impurities.

This work examines the chemical synthesis of 3,4-methylenedioxy-N-methylamphetamine (MDMA) from piperonal prepared via a catalytic ruthenium tetroxide oxidation of piperine extracted from black pepper. A variety of oxidation conditions were experimented with including different solvent systems and co-oxidants. A sample of prepared piperonal was successfully converted into MDMA via 3,4-methylenedioxyphenyl-2-nitropropene (MDP2NP) and 3,4-methylenedioxyphenyl-2-propanone (MDP2P) and the impurities within each product characterised by GC-MS to give a contaminant profile of the synthetic pathway. Interestingly, it was discovered that a chlorinated analogue of piperonal (6-chloropiperonal) was created during the oxidation process by an as yet unknown mechanism. This impurity reacted alongside piperonal to give chlorinated analogues of each precursor, ultimately yielding 2-chloro-4,5-methylenedioxymethamphetamine (6-Cl-MDMA) as an impurity within the MDMA sample. The methodology developed is a simple way to synthesise a substantial amount of precursor material with easy to obtain reagents. The results also show that chlorinated MDMA analogues, previously thought to be deliberately included adulterants, may in fact be route specific impurities with potential application in determining the origin and synthesis method of seized illicit drugs.

Crystals and tablets in the Spanish ecstasy market 2000-2014: Are they the same or different in terms of purity and adulteration?

BACKGROUND: Although 3,4-methylenedioxymethamphetamine (MDMA) has a long history in recreational settings, research on its composition (purity and adulteration) has focused only on tablets even though crystal format is readily available for users. METHODS: Drug specimens collected between January 2000 and December 2014 were analyzed at Energy Control's facilities. All samples were voluntarily provided by drug users. Sample identification was made with thin layer chromatography and gas chromatography coupled to mass spectrometry, and quantification with ultraviolet spectrophotometry (only in unadulterated samples). RESULTS: Between January 2000 and December 2014, 6200 samples purchased as ecstasy by their users were analyzed. Crystals were the most frequent format (60.6%) followed by tablets (38.8%). During the study period, the proportion of samples containing only MDMA was higher in crystals than in tablets. Compared with tablets, adulterated crystal samples contained the same number of adulterants but more combinations of different substances. Although caffeine was commonly detected as adulterant both in crystals and tablets, other substances such as phenacetin, lidocaine, dextrometorphan or methamphetamine were detected almost exclusively in crystal samples. The amount of MDMA in crystal samples remained stable unlike tablets for which a huge increase in MDMA dose was observed since 2010. CONCLUSION: Crystal samples of ecstasy showed clear differences compared to ecstasy tablets and this must be taken into account both in research and harm reduction.

Alucinógenos en las culturas precolombinas mesoamericanas / Hallucinogenic drugs in pre-Columbian Mesoamerican cultures

Introducción: El continente americano es rico en hongos y plantas psicoactivas, y numerosas culturas precolombinas mesoamericanas las emplearon con fines mágicos, terapéuticos y religiosos. Objetivos: Se revisan las evidencias arqueológicas, etnohistóricas y etnográficas del uso de sustancias alucinógenas en Mesoamérica. Resultados: Cactus, plantas y hongos alucinógenos se utilizaron para provocar estados alterados del nivel de conciencia en ceremonias rituales y curativas. Los mayas ingerían el balché (hidromiel y extracto de Lonchocarpus) en ceremonias grupales para lograr la embriaguez. También emplearon enemas rituales con sustancias psicoactivas para inducir estados de trance.Olmecas, zapotecas, mayas y aztecas usaron el peyote, los hongos alucinógenos (teonanacatl: Psylocibe spp.) y las semillas de ololiuhqui (Turbina corymbosa), que contienen mescalina, psilocibina y amida del ácido lisérgico, respectivamente. La piel del sapo Bufo spp. contiene bufotoxinas, con propiedades alucinógenas y fue usado desde el periodo olmeca. El toloache (Datura estramonio), el tabaco silvestre (Nicotiana rustica), el lirio de agua (Nymphaea ampla) y la hoja de la pastora (Salvia divinorum) se utilizaron por sus efectos psicotropos. Piedra fúngicas de 3.000 anos de antigüedad se han encontrado en contextos rituales en Mesoamérica. Las evidencias arqueológicas del uso del peyote se remontan a más de 5.000 anos. Diversos cronistas, entre ellos Fray Bernardino de Sahagún, relataron sus efectos en el siglo xvi. Conclusiones: El empleo de sustancias psicotrópicas fue muy común en las sociedades precolombinas mesoamericanas. En la actualidad chamanes y curanderos locales las siguen usando en ceremonias rituales

Objectives: The archaeological, ethno-historical and ethnographic evidence of the use of hallucinogenic substances in Mesoamerica is reviewed. Results: Hallucinogenic cactus, plants and mushrooms were used to induce altered states of consciousness in healing rituals and religious ceremonies. The Maya drank balché (a mixture of honey and extracts of Lonchocarpus) in group ceremonies to achieve intoxication. Ritual enemas and other psychoactive substances were also used to induce states of trance. Olmec, Zapotec, Maya and Aztec used peyote, hallucinogenic mushrooms (teonanacatl: Psilocybe spp) and the seeds of ololiuhqui (Turbina corymbosa), that contain mescaline, psilocybin and lysergic acid amide, respectively. The skin of the toad Bufo spp contains bufotoxins with hallucinogenic properties, and was used since the Olmec period. Jimson weed (Datura stramonium), wild tobacco (Nicotiana rustica), water lily (Nymphaea ampla) and Salvia divinorum were used fortheir psychoactive effects. Mushroom stones dating from 3000 BC have been found in ritual contexts in Mesoamerica. Archaeological evidence of peyote use dates back to over 5000 years. Several chroniclers, mainly Fray Bernardino de Sahagún, described their effects in the sixteenth century. Conclusions: The use of psychoactive substances was common in pre-Columbian Mesoamerican societies. Today, local shamans and healers still use them in ritual ceremonies in Mesoamerica

GC-MS and GC-IRD studies on brominated dimethoxyamphetamines: regioisomers related to 4-Br-2,5-DMA (DOB).

A series of regioisomeric bromodimethoxyamphetamines have mass spectra essentially equivalent to the controlled drug substance 4-Br-2,5-dimethoxyamphetamine (4-Br-2,5-DMA; DOB); all have molecular weight of 274 and major fragment ions in their electron ionization mass spectra at m/z 44 and m/z 230/232. The trifluoroacetyl, pentafluoropropionyl and heptafluorobutryl derivatives of the primary regioisomeric amines were prepared and evaluated in gas chromatography-mass spectrometry (GC-MS) studies. The mass spectra for these derivatives did not show unique fragment ions for specific identification of individual isomers. However, the mass spectra do serve to divide the compounds into three groups, depending on their base peak. Gas chromatography with infrared detection (GC-IRD) provides direct confirmatory data for the identification of the designer drug 4-bromo-2,5-dimethoxyamphetamine from the other regioisomers involved in the study. The perfluoroacylated derivatives of the six regioisomeric bromodimethoxyamphetamines were successfully resolved on non-polar stationary phases such as a 100% dimethylpolysiloxane stationary phase (Rtx-1) and 50% phenyl - 50% methyl polysiloxane (Rxi-50).

Enzyme-assisted synthesis of the glucuronide conjugate of psilocin, an hallucinogenic component of magic mushrooms.

An enzyme-assisted synthesis of psilocin glucuronide (PCG), a metabolite excreted in the urine of magic mushroom (MM) users, is described. In the presence of Aroclor 1254 pretreated rat liver microsomes, psilocin and the cofactor UDPGA were incubated for 20 h. Purification by HPLC gave PCG in 19% yield (3.6 mg). The compound structure was characterized by MS and NMR. The milligram amounts of PCG produced by this method will allow the direct identification and quantification of PCG in the urine of MM users.

Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A.

As part of our continuing efforts toward more fully understanding the structure-activity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels-Alder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure-activity relationships of furan-containing natural products.

Characterization of the synthesis of N,N-dimethyltryptamine by reductive amination using gas chromatography ion trap mass spectrometry.

The present study established an impurity profile of a synthetic route to the hallucinogenic N,N-dimethyltryptamine (DMT). The synthesis was carried out under reductive amination conditions between tryptamine and aqueous formaldehyde in the presence of acetic acid followed by reduction with sodium cyanoborohydride. Analytical characterization of this synthetic route was carried out by gas chromatography ion trap mass spectrometry using electron- and chemical-ionization modes. Methanol was employed as a liquid CI reagent and the impact of stoichiometric modifications on side-products formation was also investigated. Tryptamine 1, DMT 2, 2-methyltetrahydro-ß-carboline (2-Me-THBC, 3), N-methyl-N-cyanomethyltryptamine (MCMT, 4), N-methyltryptamine (NMT, 5), 2-cyanomethyl-tetrahydro-ß-carboline (2-CM-THBC, 6) and tetrahydro-ß-carboline (THBC, 7) have been detected under a variety of conditions. Replacement of formaldehyde solution with paraformaldehyde resulted in incomplete conversion of the starting material whereas a similar replacement of sodium cyanoborohydride with sodium borohydride almost exclusively produced THBC instead of the expected DMT. Compounds 1 to 7 were quantified and the limits of detection were 28.4, 87.7, 21.5, 23.4, 41.1, 36.6, and 34.9 ng mL(-1), respectively. The limits of quantification for compounds 1 to 7 were 32.4, 88.3, 25.4, 24.6, 41.4, 39.9, and 37.0 µg mL(-1), respectively. Linearity was observed in the range of 20.8-980 µg mL(-1) with correlation coefficients > 0.99. The application holds great promise in the area of forensic chemistry where development of reliable analytical methods for the detection, identification, and quantification of DMT are crucial and also in pharmaceutical analysis where DMT might be prepared for use in human clinical studies.