Synthetic Tryptamines Research Articles

Recent Development of Zolmitriptan Formulation in Migraine Therapy: Production, Metabolism and Pharmaceutical Aspects.

The triptans class of pharmaceuticals, which was created to treat acute migraine, is made up of indole-containing drugs that bind to a subset (1B/1D) of 5-hydroxytryptamine receptors and are agonists of serotonin receptors. At the moment, naratriptan, eletriptan, zolmitriptan, rizatriptan, almotriptan, and frovatriptan are the seven types of triptans available on the market. Among these are the FDA-approved triptans, Zolmitriptan and Sumatriptan, which are selective serotonin (5-hydroxytryptamine) agonists. Zolmitriptan, a synthetic tryptamine derivative and a well-known member of the triptan family, is available as an orally disintegrating tablet, nasal spray, and tablet. There are melt formulations of rizatriptan and zolmitriptan available on the market that are easier to use and absorb, comparable to regular pills. Recently, the FDA approved zolmitriptan, a medication with tolerability comparable to sumatriptan. Whereas zolmitriptan is only available as an oral melt or tablet, sumatriptan is available as a nasal spray, oral preparation, or self-injectable kit. The only known antimigraine drugs that were widely utilized before the triptan period were ergotamine and dihydroergotamine. However, zolmitriptan binds to plasma proteins only 25% of the time because of significant first-pass degradation. Researchers have looked into fresh ideas for solving this issue and innovations to overcome its pharmacokinetic difficulties. This article emphasizes the role of zolmitriptan in the treatment of migraines, highlighting its pharmacological properties, production, metabolism, and structural features.

Metabolite markers for three synthetic tryptamines N-ethyl-N-propyltryptamine, 4-hydroxy-N-ethyl-N-propyltryptamine, and 5-methoxy-N-ethyl-N-propyltryptamine.

N-Ethyl-N-propyltryptamine (EPT), 4-hydroxy-N-ethyl-N-propyltryptamine (4-OH-EPT), and 5-methoxy-N-ethyl-N-propyltryptamine (5-MeO-EPT) are new psychoactive substances classified as tryptamines, sold online. Many tryptamines metabolize rapidly, and identifying the appropriate metabolites to reveal intake is essential. While the metabolism of 4-OH-EPT and 5-MeO-EPT are not previously described, EPT is known to form metabolites by indole ring hydroxylation among others. Based on general knowledge of metabolic patterns, 5-MeO-EPT is also expected to form ring hydroxylated EPT (5-OH-EPT). In the present study, the aim was to characterize the major metabolites of EPT, 4-OH-EPT, and 5-MeO-EPT, to provide markers for substance identification in forensic casework. The tryptamines were incubated with pooled human liver microsomes at 37°C for up to 4 h. The generated metabolites were separated and detected by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry analysis. The major in vitro EPT metabolites were formed by hydroxylation, N-dealkylation, and carbonylation. In comparison, 4-OH-EPT metabolism was dominated by double bond formation, N-dealkylation, hydroxylation, and carbonylation in vitro and hydroxylation or carbonylation combined with double bond loss, carbonylation, N-dealkylation, and hydroxylation in vivo. 5-MeO-EPT was metabolized by O-demethylation, hydroxylation, and N-dealkylation in vitro. The usefulness of the characterized metabolites in forensic casework was demonstrated by identification of unique metabolites for 4-OH-EPT in a human postmortem blood sample with suspected EPT or 4-OH-EPT intoxication.

Electrochemistry of the synthetic tryptamine 5-MeO-MiPT at glassy carbon and screen-printed electrodes: A rapid and simple screening method for application in forensic analysis

5-Methoxy-N-methyl-N-isopropyltryptamine (5-MeO-MiPT), also known as moxy, is a synthetic tryptamine analogue used recreationally as a hallucinogenic drug. This work investigates the electrochemical behaviour of 5-MeO-MiPT using carbon electrodes for the first time. Although 5-MeO-MiPT showed only one irreversible oxidation process at a glassy carbon electrode, many electrochemical processes were exhibited on a graphite screen-printed electrode (SPE-Gr). The oxidation reaction of 5-MeO-MiPT on both carbon electrode surfaces involves an adsorption-controlled process with the loss of one electron and one proton. A voltammetric screening method for 5-MeO-MiPT was performed in 0.1 mol L−1 phosphate buffer solution at pH 7.0 on the SPE-Gr using differential pulse adsorptive stripping voltammetry (DPAdSV). The proposed method showed a wide linear range (0.05–30.0 µmol L−1) and a sufficiently low limit of detection (0.015 µmol L−1) for application to seized forensic samples containing 5-MeO-MiPT. Good stability of the electrochemical responses for 5-MeO-MiPT detection on SPE-Gr was obtained, using the same or different electrodes (N = 3) with a relative standard deviation of less than 4.0%. Interference studies with other drugs demonstrated that the proposed sensor is selective for electrochemical screening of 5-MeO-MiPT. In addition, 5-MeO-MiPT was identified in a biological sample of synthetic urine and in real seized samples by the proposed method and confirmed by GC-MS. The analytical performance of SPE-Gr with DPAdSV for 5-MeO-MiPT detection shows great potential as a simple, fast, and selective screening method in forensic scenarios.

Microextraction by packed sorbent of synthetic tryptamines from urine and ion mobility spectrometry determination

Microextraction by packed sorbent of synthetic tryptamines from urine and ion mobility spectrometry determination

In silico prediction, human hepatocyte metabolism, LC-HRMS/MS analysis, and targeted/nontargeted data-mining to characterize 4-acetoxy-N,N-diisopropyl-tryptamine metabolism

Tryptamine intoxications and fatalities are increasing, although these novel psychoactive substances (NPS) are not controlled in most countries. There are few data on the metabolic pathways and enzymes involved in tryptamines biotransformation. 4-acetoxy- N,N -diisopropyltryptamine (4-AcO-DiPT) is a synthetic tryptamine related to 4-hydroxy- N,N -diisopropyltryptamine (4-OH-DiPT), 4-acetyloxy- N,N -dipropyltryptamine (4-AcO-DPT) and 4-acetoxy- N,N -dimethyltryptamine (4-AcO-DMT). The aim was to determine the best 4-AcO-DiPT metabolites to identify 4-AcO-DiPT consumption through human hepatocyte metabolism and high-resolution mass spectrometry. 4-AcO-DiPT metabolites were predicted in silico with GLORYx freeware to assist in metabolite identification. 4-AcO-DiPT was incubated with 10-donor-pooled human hepatocytes, and sample analysis performed with reversed-phase liquid chromatography coupled with high-resolution tandem mass spectrometry (LC-HRMS/MS) in positive- and negative-ion modes. LC-HRMS/MS raw data were separately processed with targeted and nontargeted data-mining. A total of 47 phase I and II metabolites were predicted, and six metabolites were identified after 3 h incubation following ester hydrolysis, O-glucuronidation, O-sulfation, N-oxidation and N-dealkylation. All second-generation metabolites derived from the only first-generation metabolite detected after ester hydrolysis (4-OH-DiPT). Interestingly, the most intense metabolite (4-OH-DiPT) was also detected in the control samples without hepatocytes at 0 and 3 h and at 0 h incubation with hepatocytes but at much lower intensity than after 3 h incubation with hepatocytes, meaning that, although 4-OH-DiPT is formed through enzymatic reaction, it is also spontaneously formed during incubation to a lesser extent. This indicates that 4-OH-DiPT formation was overestimated in our experiments. When analyzing authentic samples, digestion (with β-glucuronidase/sulfatase) is preferred to increase the 4-OH-DiPT signal. Since the parent drug is most likely degraded and the acetyl group is eliminated quickly, toxicologists could report 4-OH-DiPT positive cases that actually were from 4-AcO-DiPT intake. The second most intense metabolite was 4-OH-iPT-sulfate followed by 4-OH-DiPT-glucuronide, indicating that glucuronidation and sulfation are common in this tryptamine's metabolic pathway. Others propose that tryptamines do not have a common metabolic pathway and that metabolism changes depending on the nature and position of their substituents, with demethylation, hydroxylation and dealkylation the most common phase I reactions, followed by glucuronidation or sulfation. 4-OH-DiPT, 4-OH-iPT and 4-OH-DiPT-N-oxide are proposed as biomarkers of 4-AcO-DiPT consumption, but the rapid enzymatic hydrolysis and lower spontaneous hydrolysis of 4-AcO-DiPT to 4-OH-DiPT might create a problem in discerning 4-AcO-DiPT from 4-OH-DiPT consumption. If the parent drug is present even in low concentrations, the ingested drug would be clear, but there is no available information regarding detection of this drug in authentic samples. These results require in vivo confirmation, which is challenging due to the small number of 4-AcO-DiPT seizures in recent years. Psychedelic tryptamine use is low but increasing, raising the importance of laboratory identification of specific metabolites to verify intake and identify potential public health NPS outbreaks. Since the parent drug is rapidly hydrolyzed and it is currently unknown whether 4-AcO-DiPT is present in authentic biological samples, identifying its metabolites is highly useful throughout, but especially late in its time course. 4-OH-DiPT, 4-OH-iPT and 4-OH-DiPT- N -oxide are optimal biomarkers to identify 4-AcO-DiPT consumption.

Human Hepatocyte 4-Acetoxy-N,N-Diisopropyltryptamine Metabolite Profiling by Reversed-Phase Liquid Chromatography Coupled with High-Resolution Tandem Mass Spectrometry.

Tryptamine intoxications and fatalities are increasing, although these novel psychoactive substances (NPS) are not controlled in most countries. There are few data on the metabolic pathways and enzymes involved in tryptamine biotransformation. 4-acetoxy-N,N-diisopropyltryptamine (4-AcO-DiPT) is a synthetic tryptamine related to 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT), 4-acetyloxy-N,N-dipropyltryptamine (4-AcO-DPT), and 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT). The aim of this study was to determine the best 4-AcO-DiPT metabolites to identify 4-AcO-DiPT consumption through human hepatocyte metabolism and high-resolution mass spectrometry. 4-AcO-DiPT metabolites were predicted in silico with GLORYx freeware to assist in metabolite identification. 4-AcO-DiPT was incubated with 10-donor-pooled human hepatocytes and sample analysis was performed with reversed-phase liquid chromatography coupled with high-resolution tandem mass spectrometry (LC-HRMS/MS) in positive- and negative-ion modes. Software-assisted LC-HRMS/MS raw data mining was performed. A total of 47 phase I and II metabolites were predicted, and six metabolites were identified after 3 h incubation following ester hydrolysis, O-glucuronidation, O-sulfation, N-oxidation, and N-dealkylation. All second-generation metabolites were derived from the only first-generation metabolite detected after ester hydrolysis (4-OH-DiPT). The metabolite with the second-most-intense signal was 4-OH-iPT-sulfate followed by 4-OH-DiPT-glucuronide, indicating that glucuronidation and sulfation are common in this tryptamine’s metabolic pathway. 4-OH-DiPT, 4-OH-iPT, and 4-OH-DiPT-N-oxide are suggested as optimal biomarkers to identify 4-AcO-DiPT consumption.

Tentative identification of in vitro metabolites of O-acetylpsilocin (psilacetin, 4-AcO-DMT) by UHPLC-Q-Orbitrap MS.

4-Acetoxy-N,N-dimethyltryptamine (4-AcO-DMT, psilacetin, O-acetylpsilocin) is a synthetic tryptamine with psychedelic properties. Psilacetin may also act as precursor drug of psilocin, similar to psilocybin, but little is known about its metabolism. In this study, the phase I and phase II in vitro metabolism of 4-AcO-DMT was investigated with pooled human liver microsomes, and the reaction mixture was analyzed using liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry. Fifteen metabolites were formed after incubation of pooled human liver microsomes with 4-AcO-DMT (12 phase I metabolites and 3 phase II metabolites). The proposed metabolite structures were based on accurate mass analysis and MS/MS fragmentation patterns. The biotransformations included hydrolysis, hydroxylation, N-demethylation, oxidation, and conjugation with glucuronic acid. The hydrolysis metabolite was the most abundant compound. For the development of new methods for the identification of 4-AcO-DMT consumption, the beta-hydroxylation metabolite of 4-AcO-DMT (M2-1) is recommended as a biomarker. The data reported in this work might be applicable to metabolic transformation of 4-AcO-DMT in vivo and also forensically helpful.

Can the Intake of a Synthetic Tryptamine be Detected Only by Blood Plasma Analysis? A Clinical Toxicology Case Involving 4-HO-MET.

Tryptamines represent a group of hallucinogenic new psychoactive substances with increasing prevalence. Unfortunately, only limited data concerning their toxicology and bioanalysis are available as tryptamines are not included in routine screening procedures in many laboratories. In order to expand the current knowledge, we report a non-fatal clinical toxicology case involving the synthetic tryptamine 4-HO-MET (4-hydroxy-N-methyl-N-ethyl-tryptamine, 3-{2-[ethyl(methyl)amino]ethyl}-1H-indol-4-ol, metocin or methylcybin). As only blood of the intoxicated patient was available, our systematic blood plasma screening approaches based on gas chromatography-mass spectrometry (GC-MS) and liquid chromatography (LC) coupled to low-resolution linear ion trap mass spectrometry (ITMSn) or high-resolution tandem mass spectrometry (HRMS-MS) were conducted. The ingestion of the synthetic tryptamine 4-HO-MET could be revealed by blood plasma analysis using both LC-based systematic screening approaches. However, 4-HO-MET was not detected by GC-MS. Furthermore, the detection of metabolites, which may be used to confirm an intake of the parent compound 4-HO-MET, was only successful using LC-HRMS-MS most probably due to its increased sensitivity compared to LC-ITMSn. A total of four metabolites were detected in blood, including N-demethyl-, oxo- and hydroxy-4-HO-MET, as well as the N-oxide. Finally, LC-HRMS-MS analysis revealed a plasma concentration of 193 ng/mL for 4-HO-MET using the standard addition method. The presented data may help clinical and forensic toxicologists with the interpretation of future cases involving synthetic tryptamines, especially if only blood samples are available.

Cardiotoxic effects of [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol

Two synthetic tryptamines, namely [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate (4-AcO-DET) and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol (4-HO-MET), are abused by individuals seeking recreational hallucinogens. These new psychoactive substances (NPSs) can cause serious health problems because their adverse effects are mostly unknown. In the present study, we evaluated the cardiotoxicity of 4-AcO-DET and 4-HO-MET using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, electrocardiography (ECG), and the human ether-a-go-go-related gene (hERG) assay. In addition, we analyzed the expression level of p21 (CDC42/RAC)-activated kinase 1 (PAK1), which is known to play various roles in the cardiovascular system. In the MTT assay, 4-AcO-DET- and 4-HO-MET-treated H9c2 cells proliferated in a concentration-dependent manner. Moreover, both substances increased QT intervals (as determined using ECG) in Sprague–Dawley rats and inhibited potassium channels (as verified by the hERG assay) in Chinese hamster ovary cells. However, there was no change in PAK1 expression. Collectively, the results indicated that 4-AcO-DET and 4-HO-MET might cause adverse effects on the cardiovascular system. Further studies are required to confirm the relationship between PAK1 expression and cardiotoxicity. The findings of the present study would provide science-based evidence for scheduling the two NPSs.

Application of hair analysis to document illegal 5-methoxy-N,N-dissopropyltrptamine (5-MeO-DiPT) use

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT) is a designer hallucinogen that is a synthetic tryptamine derivative. It is highly abused and is involved in criminal activities because of its psychotropic properties. Herein, we presented an UHPLC-MS/MS method allowing for the qualitative and quantitative determination of 5-MeO-DiPT in human hair. The hair was first decontaminated and then cut into pieces. Thirty milligrams of hair samples was pulverized below 4°C in the presence of 0.5mL deionized water containing 0.1% formic acid. After centrifuging twice, 5μL of supernatant was injected into the LC–MS/MS system. A T3 column (100mm×2.1mm, 1.8μm) was used, and mobile phases consisted of 20mmol/L ammonium acetate, 5% acetonitrile and 0.1% formic acid in water (solvent A) and acetonitrile (solvent B). The gradient elution was used at a flow rate of 0.3mL/min. The resulting calibration curve for 5-MeO-DiPT was y=281.50213x+0.00231 (R2=0.992), the limit of detection (LOD) was 0.05pg/mg, and the lower limit of quantification (LLOQ) was 0.1pg/mg. The accuracy was between 92.1% and 105.6%, and the intra- and interday precision, recovery and matrix effect were acceptable. The validated method was successfully used in 106 real cases, and the concentration of 5-MeO-DiPT in hair samples of these suspected users was 0.2–7532.5pg/mg. These cases present data to document illegal 5-MeO-DiPT use.

Four Novel Synthetic Tryptamine Analogs Induce Head-Twitch Responses and Increase 5-HTR2a in the Prefrontal Cortex in Mice.

Tryptamines are monoamine alkaloids with hallucinogenic properties and are widely abused worldwide. To hasten the regulations of novel substances and predict their abuse potential, we designed and synthesized four novel synthetic tryptamine analogs: Pyrrolidino tryptamine hydrochloride (PYT HCl), Piperidino tryptamine hydrochloride (PIT HCl), N,N-dibutyl tryptamine hydrochloride (DBT HCl), and 2-Methyl tryptamine hydrochloride (2-MT HCl). Then, we evaluated their rewarding and reinforcing effects using the conditioned place preference (CPP) and self-administration (SA) paradigms. We conducted an open field test (OFT) to determine the effects of the novel compounds on locomotor activity. A head-twitch response (HTR) was also performed to characterize their hallucinogenic properties. Lastly, we examined the effects of the compounds on 5-HTR1a and 5-HTR2a in the prefrontal cortex using a quantitative real-time polymerase chain reaction (qRT-PCR) assay. None of the compounds induced CPP in mice or initiated SA in rats. PYT HCl and PIT HCl reduced the locomotor activity and elevated the 5-HTR1a mRNA levels in mice. Acute and repeated treatment with the novel tryptamines elicited HTR in mice. Furthermore, a drug challenge involving a 7-day abstinence from drug use produced higher HTR than acute and repeated treatments. Both the acute treatment and drug challenge increased the 5-HTR2a mRNA levels. Ketanserin blocked the induced HTR. Taken together, the findings suggest that PYT HCl, PIT HCl, DBT HCl, and 2-MT HCl produce hallucinogenic effects via 5-HTR2a stimulation, but may have low abuse potential.

Investigating the ability of the microbial model Cunninghamella elegans for the metabolism of synthetic tryptamines.

Tryptamines can occur naturally in plants, mushrooms, microbes, and amphibians. Synthetic tryptamines are sold as new psychoactive substances (NPS) because of their hallucinogenic effects. When it comes to NPS, metabolism studies are of crucial importance, due to the lack of pharmacological and toxicological data. Different approaches can be taken to study in vitro and in vivo metabolism of xenobiotica. The zygomycete fungus Cunninghamella elegans (C. elegans) can be used as a microbial model for the study of drug metabolism. The current study investigated the biotransformation of four naturally occurring and synthetic tryptamines [N,N-Dimethyltryptamine (DMT), 4-hydroxy-N-methyl-N-ethyltryptamine (4-HO-MET), N,N-di allyl-5-methoxy tryptamine (5-MeO-DALT) and 5-methoxy-N-methyl-N-isoporpoyltryptamine (5-MeO-MiPT)] in C. elegans after incubation for 72hours. Metabolites were identified using liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS) with a quadrupole time-of-flight (QqTOF) instrument. Results were compared to already published data on these substances. C. elegans was capable of producing all major biotransformation steps: hydroxylation, N-oxide formation, carboxylation, deamination, and demethylation. On average 63% of phase I metabolites found in the literature could also be detected in C. elegans. Additionally, metabolites specific for C. elegans were identified. Therefore, C. elegans is a suitable complementary model to other in vitro or in vivo methods to study the metabolism of naturally occurring or synthetic tryptamines.

Proposal of 5-methoxy-N-methyl-N-isopropyltryptamine consumption biomarkers through identification of in vivo metabolites from mice

New psychoactive substances (NPS) are a new breed of synthetically produced substances designed to mimic the effects of traditional illegal drugs. Synthetic cannabinoids and synthetic cathinones are the two most common groups, which try to mimic the effects of the natural compounds 9Δ-tetrahydrocannabinol and cathinone, respectively. Similarly, synthetic tryptamines are designer compounds which are based on the compounds psilocin, N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine found in some mushrooms. One of the most important tryptamine compounds found in seizures is 5-methoxy-N,N-diisopropyltryptamine, which has been placed as controlled substance in USA and some European countries. The control of this compound has promoted the rising of another tryptamine, the 5-methoxy-N-methyl-N-isopropyltryptamine, which at the time of writing this article has not been banned yet. So, it is undeniable that this new substance should be monitored.5-methoxy-N-methyl-N-isopropyltryptamine has been reported by the Spanish Early Warning System and detected in our laboratory in two pill samples purchased in a local smart shop. This has promoted the need of stablishing consumption markers for this compound in consumers’ urine. In the present work, the metabolism and pharmacokinetic of 5-methoxy-N-methyl-N-isopropyltryptamine has been studied by an in vivo approach, using adult male mice of the inbred strain C57BLJ/6. The use of ultra-high performance liquid chromatography coupled to high resolution mass spectrometry allowed the identification of four metabolites. After the pharmacokinetic study in serum and urine, the O-demethylated metabolite and the non-metabolised parent compound are proposed as consumption markers in hydrolysed urine. Data reported in this work will help hospitals and forensic laboratories to monitor the consumption and potential intoxication cases related to this tryptamine.

Test purchase of new synthetic tryptamines via the Internet: Identity check by GC-MS and separation by HPLC

Over the past few years, a continuous alteration of the recreational drug market took place. Among other novel psychoactive drugs, new synthetic tryptamine derivatives appeared on the market. These compounds are mainly traded via the Internet, which has become an important marketplace for the sale of recreational drugs. The goal of our research was to check, if 13 new synthetic tryptamines obtained by test purchase via different online vendors meet the promised identity. Analysis was performed by GC-MS, using a common 30 m HP-5MS capillary column as stationary phase. Subsequently, a simple HPLC method for the separation of these tryptamines was developed. Therefore, the aim was to establish a method to separate a broad spectrum of trypamines simultaneously within short time. Measurements were performed by a LiChrospher® RP-18e column and a mobile phase consisting of 0.1% triethylammonium acetate buffer, methanol and acetonitrile. Both presented methods were found to be suitable for the identification as well as separation of tryptamines as the analysis times were short and the selectivity sufficient. Moreover, enantioseparation of 3 chiral tryptamine derivatives purchased via the Internet by HPLC-UV and an Astec® Cyclobond I™ 2000 as CSP was performed. All of them were sold as racemic mixtures.

Metabolism of the new psychoactive substances N,N-diallyltryptamine (DALT) and 5-methoxy-DALT and their detectability in urine by GC-MS, LC-MSn, and LC-HR-MS-MS.

N,N-Diallyltryptamine (DALT) and 5-methoxy-DALT (5-MeO-DALT) are synthetic tryptamine derivatives commonly referred to as so-called new psychoactive substances (NPS). They have psychoactive effects that may be similar to those of other tryptamine derivatives. The objectives of this work were to study the metabolic fate and detectability, in urine, of DALT and 5-MeO-DALT. For metabolism studies, rat urine obtained after high-dose administration was prepared by precipitation and analyzed by liquid chromatography-high-resolution mass spectrometry (LC-HR-MS-MS). On the basis of the metabolites identified, several aromatic and aliphatic hydroxylations, N-dealkylation, N-oxidation, and combinations thereof are proposed as the main metabolic pathways for both compounds. O-Demethylation of 5-MeO-DALT was also observed, in addition to extensive glucuronidation or sulfation of both compounds after phase I transformation. The cytochrome P450 (CYP) isoenzymes predominantly involved in DALT metabolism were CYP2C19, CYP2D6, and CYP3A4; those mainly involved in 5-MeO-DALT metabolism were CYP1A2, CYP2C19, CYP2D6, and CYP3A4. For detectability studies, rat urine was screened by GC-MS, LC-MS(n), and LC-HR-MS-MS after administration of low doses. LC-MS(n) and LC-HR-MS-MS were deemed suitable for monitoring consumption of both compounds. The most abundant targets were a ring hydroxy metabolite of DALT, the N,O-bis-dealkyl metabolite of 5-MeO-DALT, and their glucuronides. GC-MS enabled screening of DALT by use of its main metabolites only.

Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes.

Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the USA. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin 2A (5-HT₂A) receptors. This study evaluated the interaction of a series of synthetic tryptamines with biogenic amine neurotransmitter transporters and with serotonin (5-HT) receptor subtypes implicated in psychedelic effects. Neurotransmitter transporter activity was determined in rat brain synaptosomes. Receptor activity was determined using calcium mobilization and DiscoveRx PathHunter assays in HEK293, Gα16-CHO, and CHOk1 cells transfected with human receptors. Twenty-one tryptamines were analyzed in transporter uptake and release assays, and 5-HT₂A, serotonin 1A (5-HT₁A), and 5-HT₂A β-arrestin functional assays. Eight of the compounds were found to have 5-HT-releasing activity. Thirteen compounds were found to be 5-HT uptake inhibitors or were inactive. All tryptamines were 5-HT₂A agonists with a range of potencies and efficacies, but only a few compounds were 5-HT1A agonists. Most tryptamines recruited β-arrestin through 5-HT₂A activation. All psychoactive tryptamines are 5-HT₂A agonists, but 5-HT transporter (SERT) activity may contribute significantly to the pharmacology of certain compounds. The in vitro transporter data confirm structure-activity trends for releasers and uptake inhibitors whereby releasers tend to be structurally smaller compounds. Interestingly, two tertiary amines were found to be selective substrates at SERT, which dispels the notion that 5-HT-releasing activity is limited only to primary or secondary amines.

Delirium Due to Intoxication from the Novel Synthetic Tryptamine 5‐MeO‐DALT

Synthetic tryptamines have gained popularity for their hallucinogenic properties, unscheduled status, and availability from "head shops" and through the internet. Here, we present a case of synthetic tryptamine-induced delirium secondary to 5-MeO-DALT ingestion in a previously healthy young male. 5-MeO-DALT led to the hospitalization of our patient after ingestion of a standard dose, presenting with extreme agitation, tachycardia, diaphoresis, and combativeness leading to physical restraint and intravenous sedation. A search of PubMed, Ovid, and Google Scholar for keywords of "5-MeO-DALT," "5-methoxy-N,N-diallyltryptamine," or "Lucy-N-Nate" found no case reports or clinical articles in the literature. Rapid emergence and commercialization of this novel synthetic tryptamine 5-MeO-DALT points to the importance of health care and forensic professionals keeping abreast of the latest drugs of abuse and their clinical features. The authors hope this report leads the way in disseminating the potential risks associated with unscheduled and unregulated substances, synthetic tryptamines such as 5-MeO-DALT in particular.

A qualitative/quantitative approach for the detection of 37 tryptamine-derived designer drugs, 5 β-carbolines, ibogaine, and yohimbine in human urine and plasma using standard urine screening and multi-analyte approaches

The first synthetic tryptamines have entered the designer drug market in the late 1990s and were distributed as psychedelic recreational drugs. In the meantime, several analogs have been brought onto the market indicating a growing interest in this drug class. So far, only scarce analytical data were available on the detectability of tryptamines in human biosamples. Therefore, the aim of the presented study was the development and full validation of a method for their detection in human urine and plasma and their quantification in human plasma. The liquid chromatography-linear ion trap mass spectrometry method presented covered 37 tryptamines as well as five β-carbolines, ibogaine, and yohimbine. Compounds were analyzed after protein precipitation of urine or fast liquid-liquid extraction of plasma using an LXQ linear ion trap coupled to an Accela ultra ultra high-performance liquid chromatography system. Data mining was performed via information-dependent acquisition or targeted product ion scan mode with positive electrospray ionization. The assay was selective for all tested substances with limits of detection in urine between 10 and 100ng/mL and in plasma between 1 and 100ng/mL. A validated quantification in plasma according to international recommendation could be demonstrated for 33 out of 44 analytes.

An analysis of the synthetic tryptamines AMT and 5-MeO-DALT: Emerging ‘Novel Psychoactive Drugs’

Novel Psychoactive Drugs (NPD) can be sold without restriction and are often synthetic analogues of controlled drugs. The tryptamines are an important class of NPD as they bind to the various serotonin (5-HT) receptor subtypes and cause psychosis and hallucinations that can lead to injury or death through misadventure. Here we report on the structure elucidation and receptor binding profiles of two widely marketed tryptamine-derived NPDs, namely alpha-methyl-tryptamine and 5-methoxy-N,N-diallyl-tryptamine.

The Use of Synthetic Cathinones and Tryptamines in a Psychiatric Population

The use of Synthetic Cathinones and Tryptamines in a Psychiatric Population A new wave of designer drugs is emerging in both emergency room (ER) patients and the community at large. These drugs commonly known and sold as “bath salts” produce toxic effects as well as disturbing psychopathological symptoms. These drugs are a synthetic modification of the naturally occurring alkaloid cathinone, which can be extracted from the leaves of Catha edulis, commonly known as the khat plant. The synthetic cathinones such as methylone; 3, 4 methylendioxyprovalerone (MDPV); mephedrone; and ethylone are commonly sold under various names such as “Ivory Wave”, “Vanilla Sky” and “Bliss”. The tryptamines discussed in this paper are a group of psychedelic substances primarily regarded for their hallucinogenic properties.Commonly known tryptamines include LSD and psilocybin found in magic mushroom. Less commonly know tryptamines such as DMT, AMT and 5MEODiPT are the compounds of interest in this paper.