ArticleLiterature Review

The recreational tryptamine 5-MeO-DALT (N,N-diallyl-5-methoxytryptamine): A brief review

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Abstract

5-MeO-DALT (N,N-diallyl-5-methoxytryptamine) is a psychoactive substance, sold primarily over the Internet as a 'research chemical' or 'plant food'. Although details for the synthesis of this tryptamine have been available since 2004, its use as a hallucinogenic drug has been reported only occasionally in on-line user fora. It is controlled in only a few countries world-wide. There is little scientifically-based literature on the pharmacological, physiological, psychopharmacological, toxicological and epidemiological characteristics of 5-MeO-DALT. Here we review what is known about these aspects. We also report what we believe to be the first death involving the use of this substance. The case involved a man in his mid-20s who died in mid-2010. The coroner concluded that the deceased "died from injuries sustained after being hit by a lorry whilst under the influence of 5-MeODALT". It is critical that any other cases, including non-fatal instances, are documented so that a scientific evidence-base can be established for this drug.

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... 5-MeO-DALT contains two allyl groups bound to the amino group, as well as a 5-methoxy group, bound to the indole ring (3). It is also known as Foxtrot and is consumed for its hallucinogenic and entheogenic effects (5). 5-MeO-DALT poisonings are rarely reported, and this drug is not routinely tested by laboratories. ...
... In the other described cases, 5-MeO-DALT caused extreme agitation, tachycardia, diaphoresis, and rhabdomyolysis, but all patients recovered without sequelae (5,12,13). Only one death was reported but it occurred through a misadventure as the patient died from injuries sustained after being hit by a truck while under the influence of 5-MeO-DALT (5). ...
... In the other described cases, 5-MeO-DALT caused extreme agitation, tachycardia, diaphoresis, and rhabdomyolysis, but all patients recovered without sequelae (5,12,13). Only one death was reported but it occurred through a misadventure as the patient died from injuries sustained after being hit by a truck while under the influence of 5-MeO-DALT (5). ...
Article
5-MeO-DALT or 5-methoxy-N,N-diallyltryptamine is a derivative of tryptamines, consumed for its hallucinogenic and entheogenic effects. We report the case of a 46-year-old-man, presenting with a brief loss of consciousness and visual hallucinations, after the consumption of three 5-MeO-DALT tablets bought online. Liquid chromatography coupled to tandem mass spectrometry method (LC-MS/MS) was performed, and 5-Meo-DALT was quantified in both the tablets (32,5 mg per tablet, 11% of purity) and the patient’s plasma (7 ng/ml - 8 hours between the consumption and the blood sample). 5-MeO-DALT poisonings are rarely described. Given the broad availability of these products, it is important that emergency department physicians and clinical toxicologists do not overlook the possibility of the ingestion of recreational tryptamines, especially since they are not detected by most routine toxicological screening.
... Tryptamines are sold as tablets or powder and consumed through different routes of administration (Araujo et al., 2015;Corkery, Durkin, Elliott, Schifano, & Ghodse, 2012). In particular, the Psilocybe mushrooms are eaten raw or infused in tea to extract the active principles, while other tryptamines are insufflated (snorting or sniffing), inhaled, injected intravenously, ingested in capsules or wrapped in a cigarette paper, or administered rectally (Araujo et al., 2015;Corkery et al., 2012). ...
... Tryptamines are sold as tablets or powder and consumed through different routes of administration (Araujo et al., 2015;Corkery, Durkin, Elliott, Schifano, & Ghodse, 2012). In particular, the Psilocybe mushrooms are eaten raw or infused in tea to extract the active principles, while other tryptamines are insufflated (snorting or sniffing), inhaled, injected intravenously, ingested in capsules or wrapped in a cigarette paper, or administered rectally (Araujo et al., 2015;Corkery et al., 2012). Generally, tryptamine users are young males; 5-MeO-DIPT is frequently abused by homosexuals (Araujo et al., 2015). ...
... More common effects after use of tryptamines are hallucinogenic effects accompanied by euphoria, increased body energy, difficulty in walking due to loss of limbs control, and "out of body" experiences (Corkery et al., 2012;Nelson et al., 2014). At high doses vasoconstriction, enhanced blood pressure, rapid heartbeat, headache, sweating, bruxism, dilated pupils, and paranoia (i.e., bad trip) may occur along with anxiety, nausea, strong desire to eat, increased alertness, and agitation (Araujo et al., 2015;Corkery et al., 2012). ...
Chapter
Usually considered as legal replacement for regulated products, novel psychoactive substances (NPS) represent worldwide an underestimate health risk. Freely available on the Internet, NPS are still legal in some countries, advertised as safe substances, and in most cases undetectable by standard drug-screening tests, which renders NPS very popular and appealing to drug users. They typically induce more frequent and severe negative effects than the precursor drug they are supposed to mimic, and are associated with severe toxicity and fatal intoxications. In this chapter we illustrate and discuss the pharmacology and toxicology of the most common classes of NPS, that is, hallucinogens, stimulants, dissociative drugs, prescribed products, and performance- and image-enhancing drugs (PIEDs). Despite growing regulatory control measures, use of NPS is extensive and represents an ever-evolving health and legal concern. Social and health professionals should maintain a high degree of alertness for NPS use and their possible psychiatric effects among vulnerable people.
... Tryptamines products are usually distributed in the form of powder or tablets. There are many different ways of tryptamines consumption like smoking, insufflation, IV or IM injection [56,92]. Accessible methods of synthesis from internet make tryptamines a very popular designer drug, especially among young adults [90,93,94]. ...
... Similar to the designer drugs, there is no precise antidote to cure tryptamines intoxication. Supportive care and vital signs monitoring are the first line therapy provide to patients [90][91][92][93][94][95][96][97][98][99][100][101][102][103][104]. ...
Chapter
Different botanical derived or synthetic addictive substances have been "misused" and/or "abused" for centuries around the world. To overcome the abuse by these substances, strict legal laws were constituted globally. However, novel and drugs with chemical structures similar to illegal psychoactive drugs substances (with a slight structural change) were manufactured in undercover laboratories to have the same or augmented psycho-stimulatory effects. Currently, the major classes of designer drugs are piperazines, cathinones, synthetic cannabinoids, synthetic opi-oids, tryptamines, and phenethylamines. These classes of designer drugs have shown to elicit significant psychostimulatory effect by a different mechanism of action. They have shown to affect various monoaminergic neurotransmission and induce severe toxic effect, which if not treated properly, can be detrimental leading to death. In this book chapter, we have explained the chemical structural aspects of various designer drugs, their mechanism of action, side-effect and possible therapeutic interventions.
... Furthermore, indole-based derivatives seem to play a major role in preventing oxidative effects in rats during exercise [61]. Tryptamine (M3) is formed by the catabolism of tryptophan by gut microbiota [62], and it was found that it acts on the parts of the brain releasing serotonin, enhancing the serotoninergic activity [63]. Therefore, it seems the proposed supplementation enhances the indole derivatives either through the human metabolism or by their production in the gut. ...
Article
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Oleuropein (OE) is a secoiridoid glycoside occurring mostly in the Oleaceae family and presenting several pharmacological properties, including hypolipidemic and antioxidant properties. Based on these, several dietary supplements containing olive leaf extracts enriched with OE are commercially available in many countries. The current study aimed to examine the effect of supplementation with such an extract on the serum and urine metabolome of young healthy male athletes. For this purpose, applying a randomized, balanced, double-blind study, nine young, healthy males (physical education students) received either a commercially prepared extract or placebo for one week, followed by a two-week washout period; then, they were subsequently dosed with the alternate scheme (crossover design). Urine and serum samples were analyzed using UHPLC-HRMS, followed by evaluation with several multivariate methods of data analysis. The data were interpreted using a multilevel metabolomic approach (multilevel-sPLSDA) as it was found to be the most efficient approach for the study design. Metabolic pathway analysis of the most affected metabolites revealed that tryptophan and acylcarnitine’s biochemistries were most influenced. Furthermore, several metabolites connected to indole metabolism were detected, which may indicate enhanced serotonin turnover. Phenylethylamine and related metabolites, as well as estrone, were connected to enhanced performance. In addition, possible changes to the lipidemic profile and the blood and urine redox statuses were investigated.
... Research has shown, however, increased locomotor activity in rodents when administrating 5-MeO-DALT. It is a controlled substance in several countries (Corkery, Durkin, et al., 2012;Gatch et al., 2017). Dextromethorphan ...
Article
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The world market for food supplements is large and is driven by the claims of these products to, for example, treat obesity, increase focus and alertness, decrease appetite, decrease the need for sleep or reduce impulsivity. The use of illegal compounds in food supplements is a continuous threat, certainly because these compounds and products have not been tested for safety by competent authorities. It is therefore of the utmost importance for the competent authorities to know when new products are being marketed and to warn users against potential health risks. In this study, an approach is presented to detect new and unknown stimulants in food supplements using machine learning. More than 20 new stimulants were identified from two different data sources, namely scientific literature applying word embedding on > 2 million abstracts and articles from formal and social media on the world wide web using text mining. The results show that the developed approach may be suitable to detect “unknowns” in the emerging risk identification activities performed by the competent authorities, which is currently a major hurdle.
... Although today it does not have any therapeutic applicability, its popularity as a "designer drug" increased in 1990s [420]. Tryptamine derivatives can be found as a free base or salt, tablets, or powders [421,422]. ...
Article
Full-text available
The misuse of psychoactive substances is attracting a great deal of attention from the general public. An increase use of psychoactive substances is observed among young people who do not have enough awareness of the harmful effects of these substances. Easy access to illicit drugs at low cost and lack of effective means of routine screening for new psychoactive substances (NPS) have contributed to the rapid increase in their use. New research and evidence suggest that drug use can cause a variety of adverse psychological and physiological effects on human health (anxiety, panic, paranoia, psychosis, and seizures). We describe different classes of these NPS drugs with emphasis on the methods used to identify them and the identification of their metabolites in biological specimens. This is the first review that thoroughly gives the literature on both natural and synthetic illegal drugs with old known data and very hot new topics and investigations, which enables the researcher to use it as a starting point in the literature exploration and planning of the own research. For the first time, the conformational analysis was done for selected illegal drugs, giving rise to the search of the biologically active conformations both theoretically and using lab experiments.
... [95] and was seized by police in 2006 as a "plant fertilizer" or "plant food" [29]. Active oral doses ranged from 12-20 mg [101], with administration by the oral, nasal insufflation and IV routes. This drug produced dose-dependent effects 15 to 30 min after oral administration that lasted for 2 to 4 h. ...
Article
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Our understanding of tryptamines is poor due to the lack of data globally. Tryptamines currently are not part of typical toxicology testing regimens and their contribution to drug overdoses may be underestimated. Although their prevalence was low, it is increasing. There are few published data on the many new compounds, their mechanisms of action, onset and duration of action, toxicity, signs and symptoms of intoxication and analytical methods to identify tryptamines and their metabolites. We review the published literature and worldwide databases to describe the newest tryptamines, their toxicology, chemical structures and reported overdose cases. Tryptamines are 5-HT2A receptor agonists that produce altered perceptions of reality. Currently, the most prevalent tryptamines are 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT), 5-methoxy-N,N- diallyltryptamine (5-MeO-DALT) and dimethyltryptamine (DMT). From 2015 to 2020, 22 new analytical methods were developed to identify/quantify tryptamines and metabolites in biological samples, primarily by liquid chromatography tandem mass spectrometry. The morbidity accompanying tryptamine intake is considerable and it is critical for clinicians and laboratorians to be informed of the latest data on this public health threat.
... Mammalian brains contain trace amounts of tryptamine which may act as a neurotransmitter or neuromodulator (Jones, 1982). As a serotonin (5hydroxytryptamine) releasing agent and a serotonergic activity enhancer, tryptamine might receive 2 methyl groups from SAM to become dimethytryptamine (Corkery et al., 2012). Serotonin, which can receive one methyl group from SAM, has been shown to modulate gastrointestinal motility, peripheral vascular tone, cerebral vascular tone, and platelet function and has been implicated in the pathophysiology of mood disorders, emesis, migraine, irritable bowel syndrome, and pulmonary and systemic hypertension (Mohammad-Zadeh et al., 2008). ...
Article
Methionine is the second or third limiting amino acid in typical swine diets, and exogenous methionine supplementation can improve the efficiency of dietary protein utilization by swine when dietary methionine is limiting. Several feed-grade methionine products, such as DL-methionine and DL-methionine hydroxy analogue free acid, have been on the market for feed formulation. Recently, some feed-grade L-methionine products also became available on the market for swine. However, questions often asked by producers and nutritionists are whether or not more crystalline methionine should be used, and which product should be used. Although a simple answer does not exist, this paper was written to comprehensively summarize our current knowledge in methionine nutrition with an attempt to provide a single source of reference for swine nutritionists and scientists to develop more pertinent answers for different swine production systems. Therefore, in this paper, firstly, different forms of commercially available feed-grade methionine products were reviewed chronologically. Secondly, the overall effectiveness of methionine on swine growth performance was summarized. Thirdly, our current understanding of methionine metabolism in animal body was updated. Fourthly, various biochemical and physiological functions of methionine in swine were described. Lastly, dietary methionine deficiency and toxicity to the animal were pointed out. In brief, it is understood from the cellular metabolism standpoint that methionine functions primarily as a substrate for protein and peptide biosyntheses in the body. From a regulatory standpoint, methionine is an initiator amino acid for universal protein translation. Methionine is also an essential source of methyl groups for methylation of at least seven classes of bioactive compounds, such as DNA, RNA, and proteins. Meanwhile, methionine and some of its derivatives are endogenous antioxidants which can protect living cells from oxidative stress. Synthesized from methionine, a myriad of proteins and peptides are involved in immune system for maintaining animal health. Dietary methionine deficiency negatively affects pig growth performance, while supplementation of more methionine may cause toxic effects. Overall, this paper not only can endorse animal scientists to further explore the underlying metabolic and molecular mechanisms that are responsible for methionine nutrition, particularly in pigs, but also can help the field nutritionists to determine methionine requirements of pigs with different production purposes and to selectively use certain commercial methionine products during their diet formulation practice.
... Tryptamine, which is found in fungi, plants, and animals [145] are naturally occurring indole alkaloids that exhibit a broad range of medicinal and biological activities [146]. Thus, αmethyltryptamine may act as an antidepressant, a powerful psychedelic drug, a stimulant, and a monoamine oxidase inhibitor [147]. ...
Article
Full-text available
This last century, the development of new medicinal molecules represents a real breakthrough in terms of humans and animal life expectancy and quality of life. However, this success is tainted by negative environmental consequences. Indeed, the synthesis of drug candidates requires the use of many chemicals, solvents, and processes that are very hazardous, toxic, energy consuming, expensive, and generates a large amount of waste. Many large pharmaceutical companies have thus moved to using green chemistry practices for drug discovery, development, and manufacturing. One of them is the use of energy-efficient activation techniques, such as ultrasound. This review summarizes the latest most representative works published on the use of ultrasound for sustainable bioactive molecules synthesis.
... Mammalian brain contains very low concentrations (in the low ng/g range) of tryptamine, which may act as a neurotransmitter or modulator (Jones, 1982): it acts as a serotonin-releasing agent and enhances serotonergic activity (Corkery, Durkin, Elliott, Schifano, & Ghodse, 2012). ...
Article
The expression “New Synthetic Stimulants” include classes of psychoactive compounds that share subjective effects in humans such as boosted mood or euphoria, feelings of empathy or compassion, increased sociability and sex drive, perceived increased ability to learn and focus, increased energy and alertness, with unpleasant outcomes like increased blood pressure and heart rate, paranoia or aberrations, decreased appetite, raised body temperature, clenched jaw or grinding teeth, dry mouth, insomnia, hallucinations, and aggressive or violent behavior. Synthetic stimulants act in the brain by increasing concentrations of neurotransmitters, mainly dopamine and serotonin. Dopamine is involved in attention, reward, and motivation whereas serotonin is involved in generating feelings of happiness and pleasure. Synthetic stimulants act on the two brain systems to different extents, accounting for their range of effects. Noradrenaline release is also stimulated by these compounds, but to a minor degree. In any case, long‐term use of synthetic stimulants exhausts dopamine and serotonin systems in the brain. The nerve cells become desensitized to the drugs, which makes them resistant to the brain's own signaling molecules. This leads to tolerance and dependence, which can easily turn into addiction. Like classic stimulants (e.g., cocaine, methamphetamine), new synthetic stimulants can be highly addictive. This article is categorized under: • Toxicology > New Psychoactive Substances
... 7,8 While naturally occurring tryptamines are also available as dried or brewed mushrooms for oral ingestion, 1 synthetic derivatives are typically sold in tablet or powder form, and can be consumed by inhalation (smoking), ingestion (swallowing), insufflation (snorting), or intravenous injection. 7,9,10 Most tryptamines and their derivatives are classified as Schedule I drugs in the US, 11 though legislation protecting the religious use of ayahuasca was implemented in 2006 under the Religious Freedom Restoration Act. 12 Recent evidence suggests that the popularity of psychedelic tryptamines is on the rise. For example, previous reports focusing on use of new psychoactive substances (NPS) and other uncommon substances found that DMT and other tryptamines are common among NPS users in nationally representative samples, 13 as well as high-risk drug-using populations such as nightclub attendees in the US. ...
Article
Background and Objectives: The popularity of tryptamines such as N,N‐dimethyltryptamine (DMT) appears to be increasing in the United States (US), but epidemiologic literature on prevalence of use is scant. This paper aims to determine trends in prevalence and correlates of past‐year tryptamine use among a nationally representative sample of young adults in the US. Methods: Participants in the National Survey on Drug Use and Health survey were queried about past‐year use of tryptamines—specifically DMT, α‐methyltryptamine (AMT), and 5‐MeO‐DIPT (“Foxy”). Data were examined from young adults (ages 18–25), years 2007–2014 (N = 144,787). Linear trends in prevalence of past‐year tryptamine use were examined in the full sample and stratified by specific demographic and drug use characteristics. Results: Tryptamine use is rare, but increased from .2% in 2007/08 to .7% in 2013/14, a 273% relative increase (p < .001). While prevalence increased among all demographic groups, prevalence was substantially higher among individuals who use other drugs. In particular, between 2007/08 and 2013/14, prevalence of tryptamine use increased among past‐year ecstasy users (from 2.1% to 10.0%) and LSD users (from 7.0% to 15.5%) (ps < .01). Prevalence of tryptamine use tended to be higher among lifetime and past‐year users of psychedelic drugs compared to users of non‐psychedelic drugs. Conclusion: While tryptamine use is not prevalent in the general young adult population, prevalence is increasing. Users of various other drugs—particularly drugs with psychedelic effects—report higher prevalence of tryptamine use. Scientific Significance: Users of other drugs can be targeted when disseminating information about tryptamines to ensure user safety.
... 5-Methoxy-N,N-diallyltryptamine (5-MeO-DALT), for example, was first synthesized by Alexander T. Shulgin (A.T. Shulgin, personal communication), and was first marketed via the Internet in (Corkery et al., 2012). According to Shulgin, oral doses of 12e20 mg produce psychoactive effects with a rapid onset and a relatively brief duration of 2e4 h ( Shulgin and Shulgin, 2004). ...
Article
Substantial effort has been devoted toward understanding the psychopharmacological effects of tryptamine hallucinogens, which are thought to be mediated by activation of 5-HT2Aand 5-HT1Areceptors. Recently, several psychoactive tryptamines based on the N,N-diallyltryptamine (DALT) scaffold have been encountered as recreational drugs. Despite the apparent widespread use of DALT derivatives in humans, little is known about their pharmacological properties. We compared the binding affinities of DALT and its 2-phenyl-, 4-acetoxy-, 4-hydroxy-, 5-methoxy-, 5-methoxy-2-methyl-, 5-fluoro-, 5-fluoro-2-methyl-, 5-bromo-, and 7-ethyl-derivatives at 45 receptor and transporter binding sites. Additionally, studies in C57BL/6 J mice examined whether these substances induce the head twitch response (HTR), a 5-HT2A receptor-mediated response that is widely used as a behavioral proxy for hallucinogen effects in humans. Most of the test drugs bound to serotonin receptors, σ sites, α2-adrenoceptors, dopaminergic D3 receptors, histaminergic H1 receptors, and the serotonin transporter. DALT and several of the ring-substituted derivatives were active in the HTR assay with the following rank order of potency: 4-acetoxy-DALT > 5-fluoro-DALT > 5-methoxy-DALT > 4-hydroxy-DALT > DALT > 5-bromo-DALT. 2-Phenyl-DALT, 5-methoxy-2-methyl-DALT, 5-fluoro-2-methyl-DALT, and 7-ethyl-DALT did not induce the HTR. HTR potency was not correlated with either 5-HT1A or 5-HT2A receptor binding affinity, but a multiple regression analysis indicted that 5-HT2A and 5-HT1A receptors make positive and negative contributions, respectively, to HTR potency (R2 = 0.8729). In addition to supporting the established role of 5-HT2A receptors in the HTR, these findings are consistent with evidence that 5-HT1A activation by tryptamine hallucinogens buffers their effects on HTR.
... The indole ring is the important nucleus of many complex natural products having importance in drug discovery and a variety of naturally occurring, synthetic and semi-synthetic drugs are based on tryptamine skeleton. Tryptamine is found in fungi, plants and animals [2]. Tryptamine structural distinction is in approximation to the neurotransmitter serotonin and as hallucinogens and well-known drugs in these classes are DMT etc. ...
Article
Full-text available
Tryptamine the important psychotropic drug having indole ring has wider biological and pharmaceutical significance. The focus is to see the relevant and recent achievements as neurotransmitter and neuromodulator, vasoconstrictor and vasodilator, antimicrobial and antibacterial, antioxidant and antifungal agents. Tryptamine and its natural and synthetic derivative have been reported for the variety of biological significance in the above mentioned area. This review covers all these aspects in a comprehensive way
... This ritualistic and medical background might have influenced the user profile of these substances and the patterns of distribution within the market. The fact that regulated hallucinogenic tryptamines might have therapeutic effects contradicts the claims of danger (Araújo et al. 2015), despite the evidence of fatal outcomes related to their use (Corkery et al. 2012;Morano et al. 1993;Sklerov et al. 2005;Tittarelli et al. 2015). These fatal outcomes might not be inherently associated with the use of tryptamines, but, instead, with an excessive dosage and their combination with other psychoactive substances. ...
Article
New psychoactive tryptamines may be a public health risk since they intend to mimic the hallucinogenic effects of regulated psychoactive drugs. Few studies describe uses and clinical effects of unregulated new psychoactive tryptamines. This study aims (1) to explore the presence of tryptamines classified as NPS among the substances delivered for analysis to a harm-reduction organization; (2) to describe the substances found in the samples after analysis; and (3) to compare analytical results of regulated vs. non-regulated tryptamines. Samples delivered and analyzed by gas chromatography-mass spectrometry from 2006 to 2015 were included. A descriptive study of results was conducted. From 25,296 samples that were delivered, 436 were tryptamines; from these 232 (53.21%) were non-regulated. The most delivered non-regulated tryptamine was 4-AcO-DMT. A search of the PubMed database in July 2016 revealed that no studies in humans have ever been carried out with 4-AcO-DMT. Unregulated tryptamines likely contained one unadulterated substance (p ≤ 0.001). The number of samples submitted which contained tryptamines increased during the course of the study, with significant differences in client expectations vs. analysis results between the controlled and uncontrolled groups. There is a need for further research in order to prevent the potential health risks associated with their use.
... They published their experiences with more than 50 tryptamine derivatives. Besides them, few publications exist -for example, 5-MeO-DALT (N,N-diallyl-5-methoxytryptamine [25]). ...
Article
Over the last few years, hundreds of new psychoactive substances (NPS) have been identified in Europe. Apart from some herbal compounds, NPS mainly include synthetic cannabinoids and a range of new synthetic stimulants (e. g., cathinones). Synthetic NPS are often developed whilst modifying the basic chemical (e. g., phenethylamine or tryptamine) structure. Although the pharmacology and toxicology of most NPS are hardly known, they are being offered, especially online, as "bath salts," as "incense mixtures," or under other misleading labels. In addition, NPS are advertised as "legal highs," suggesting that, in contrast to substances regulated by the national laws, trading with NPS is legal. Although only little is known about the prevalence of NPS use, some of these molecules may be associated with a range of severe adverse reactions. Indeed, different from cannabis, synthetic cannabinoid users may present with epileptic seizures, loss of consciousness, and a range of persisting psychopathological disorders. Future studies should inform better-tailored management strategies.
... [8] Examples of tryptamines describedby them and subsequently appeared in case reports include 5-MeO-MIPT (5-methoxy-N-methyl-N-isopropyltryptamine) [9] and 5-MeO-DIPT (5-methoxy-N,N-diisopropyltryptamine). [10][11][12][13][14] Other tryptamines, such as 5-MeO-DALT (5-methoxy-N,Ndiallyltryptamine), [15,16] originally not described by Shulgin and Shulgin in 1997, [8] have also appeared on the market and were linked to intoxication cases. Shulgin and Shulgin [8] have also described the effects of tryptamines substituted on the 2-position of the indole ring such as 5-MeO-TMT (5-methoxy-2,N,Ntrimethyltryptamine). ...
Article
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Many N,N-dialkylated tryptamines show psychoactive properties and were encountered as new psychoactive substances. The aims of the presented work were to study the phase I and II metabolism and the detectability in standard urine screening approaches (SUSA) of 5-methoxy-2-methyl-N,N-diallyltryptamine (5-MeO-2-Me-DALT), 5-methoxy-2-methyl-N-allyl-N-cyclohexyltryptamine (5-MeO-2-Me-ALCHT), and 5-methoxy-2-methyl-N,N-diisopropyltryptamine (5-MeO-2-Me-DIPT) using GC-MS, LC-MSn, and LC-HR-MS/MS. For metabolism studies, urine was collected over a 24-h period after administration of the compounds to male Wistar rats at 20 mg/kg body weight (BW). Phase I and II metabolites were identified after urine precipitation with acetonitrile by LC-HR-MS/MS. 5-MeO-2-Me-DALT (24 phase I and 12 phase II metabolites), 5-MeO-2-Me-ALCHT (24 phase I and 14 phase II metabolites), and 5-MeO-2-Me-DIPT (20 phase I and 11 phase II metabolites) were mainly metabolized by O-demethylation, hydroxylation, N-dealkylation, and combinations of them as well as by glucuronidation and sulfation of phase I metabolites. Incubations with mixtures of pooled human liver microsomes and cytosols (pHLM and pHLC) confirmed that the main metabolic reactions in humans and rats might be identical. Furthermore, initial CYP activity screenings revealed that CYP1A2, CYP2C19, CYP2D6, and CYP3A4 were involved in hydroxylation, CYP2C19 and CYP2D6 in O-demethylation, and CYP2C19, CYP2D6, and CYP3A4 in N-dealkylation. For SUSAs, GC-MS, LC-MSn, and LC-HR-MS/MS were applied to rat urine samples after 1 or 0.1 mg/kg BW doses, respectively. In contrast to the GC-MS SUSA, both LC-MS SUSAs were able to detect an intake of 5-MeO-2-Me-ALCHT and 5-MeO-2-Me-DIPT via their metabolites following 1 mg/kg BW administrations and 5-MeO-2-Me-DALT following 0.1 mg/kg BW dosage.
... Tethering the dialkyl groups into a heterocyclic ring gave mixed results; N-pyrrolidyl had an affinity similar to N,N-dimethyltryptamine (110 vs. 75 nM, respectively), but the affinity for the N-piperidyl was much lower, at 760 nM. The N,Ndisubstituted compound 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT 18) has recently appeared as a new "legal high" on the illicit market (Corkery et al. 2012;Strano Rossi et al. 2014). Results from broad-based receptor screening led Cozzi and Daley (2016) to conclude that multiple serotonin receptors, as well as several nonserotonergic sites are important for the psychoactive effects of 18 and other N, N-diallyltryptamines. ...
Chapter
This chapter will summarize structure-activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three chemical types: tryptamines, ergolines, and phenethylamines. In the brain, the serotonin 5-HT2A receptor plays a key role in regulation of cortical function and cognition, and also appears to be the principal target for hallucinogenic/psychedelic drugs such as LSD. It is one of the most extensively studied of the 14 known types of serotonin receptors. Important structural features will be identified for activity and, where possible, those that the psychedelics have in common will be discussed. Because activation of the 5-HT2A receptor is the principal mechanism of action for psychedelics, compounds with 5-HT2A agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT2A receptors. Therefore, much of the discussion will include not only clinical or anecdotal studies, but also will consider data from animal models as well as a certain amount of molecular pharmacology where it is known.
... 56 Unlike established recreational psychedelics, some NPS hallucinogens also have stimulant properties, and these have increased risk of acute toxicity, including agitation, hallucinations, tachycardia, hypertension, hyperthermia, rhabdomyolysis, serotonin syndrome, and seizures. [57][58][59][60][61] There is currently little evidence of longer term health risks or addiction. 56 ...
Article
#### What you need to know In 2016 the Psychoactive Substances Bill banned trading but not possession of all current and future novel psychoactive substances (NPS), sometimes incorrectly called “legal highs,” in an attempt to overcome rapid proliferation of these compounds. Over 560 substances are currently monitored by the European Monitoring Centre for Drugs and Drug Addiction, with 100 new agents identified in 2015 alone. Stimulants and synthetic cannabinoids account for the vast majority and are the types most commonly clinically encountered.1 Online purchases are increasing according to the 2016 Global Drug Survey,2 potentially in response to legislative changes, as is overall NPS use: lifetime consumption was reported by 8% of younger individuals in 2015, up from 5% in 2011, with figures relatively similar between sexes and different countries.3 Professionals report feeling less confident about managing NPS compared with established recreational drugs.4 There were 15 485 accesses to UK National Poisons Information Service TOXBASE relating to “legal highs,” “branded products,” synthetic cannabinoids, and mephedrone in 2014-15.5 Regarding harms from longer term dependence, the UK National Drug Treatment Monitoring System (NDTMS) report in 2015 described 3048 and 1370 adults with documented problematic use of mephedrone and “other” NPS respectively.6 Information on NPS primarily stems from case reports and …
... 56 Unlike established recreational psychedelics, some NPS hallucinogens also have stimulant properties, and these have increased risk of acute toxicity, including agitation, hallucinations, tachycardia, hypertension, hyperthermia, rhabdomyolysis, serotonin syndrome, and seizures. [57][58][59][60][61] There is currently little evidence of longer term health risks or addiction. 56 ...
Article
#### What you need to know Identifying and managing acute drug related harms and problematic substance misuse cuts across medical specialties. Data suggest that clinicians are seeking readily accessible information on novel psychoactive substances (NPS), incorrectly known as “legal highs.” Clinicians may encounter acutely disturbed or unwell patients, individuals with harm or dependency related to chronic NPS use, and those reporting incidental consumption that might require psychoeducation and monitoring. Such assessments will have more successful and meaningful outcomes if clinicians are aware of the spectrum of NPS available and how they might affect their patient. The linked clinical update1 describes the different classes of NPS and their effects. This article provides practical advice to the non-specialist on how to approach an assessment of individuals using NPS, including examples of acute and chronic use. A sensitive, non-judgmental approach is essential. Key aspects of the history are applicable in all scenarios. Boxes 1 and 2 cover specific issues relevant to emergency and longer term presentations. Patients may be concerned about being criticised for using drugs, and they might be uncertain of, but worried about, the potential harms and available services for those using NPS. Individuals can also be fearful of legal consequences of disclosure, and the principle and limits of confidentiality should be discussed. Adopt an empathic line of questioning, such as “I can imagine it might be difficult or worrying to talk about drug/NPS use. My role is to try understand …
... Both classic tryptamine psychedelics such as N,N-dimethyltryptamine (DMT) but also synthetic tryptamine-based Bresearch chemicals^have been popular [5,6]. N,N-Diallyltryptamine (DALT) derivatives represent an important group with 5methoxy-DALT (5-MeO-DALT) being the most often reported example [7][8][9]. As such drugs may become controlled, the creation of new substances with similar chemical structures and effects is aimed at circumventing legislative restrictions [5], which Electronic supplementary material The online version of this article (doi:10.1007/s00216-016-0117-5) contains supplementary material, which is available to authorized users. ...
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Derivatives of N,N-diallyltryptamine (DALT) can be classified as new psychoactive substances. Biotransformation and detectability of 5-fluoro-DALT (5-F-DALT), 7-methyl-DALT (7-Me-DALT), and 5,6-methylenedioxy-DALT (5,6-MD-DALT) are described here. Their metabolites detected in rat urine and pooled human liver microsomes were identified by liquid chromatography (LC)–high resolution (HR)–tandem mass spectrometry (MS/MS). In addition, the human cytochrome-P450 (CYP) isoenzymes involved in the main metabolic steps were identified and detectability tested in urine by the authors’ urine screening approaches using GC-MS, LC-MSⁿ, or LC-HR-MS/MS. Aromatic and aliphatic hydroxylations, N-dealkylation, N-oxidation, and combinations could be proposed for all compounds as main pathways. Carboxylation after initial hydroxylation of the methyl group could also be detected for 7-Me-DALT and O-demethylenation was observed for 5,6-MD-DALT. All phase I metabolites were extensively glucuronidated or sulfated. Initial phase I reactions were catalyzed by CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5. Rat urine samples were analyzed following two different low-dose administrations. GC-MS was not able to monitor consumption reliably, but all three compounds are predicted to be detectable in cases of overdose. The LC-MSⁿ and LC-HR-MS/MS approaches were suitable for detecting an intake of all three compounds mainly via their metabolites. However, after the lowest dose, a reliable monitoring could only be achieved for 5-F-DALT via LC-MSⁿ and LC-HR-MS/MS and for 7-Me-DALT via LC-HR-MS/MS. The most abundant targets in both LC-MS screenings were one of two hydroxy-aryl metabolites and both corresponding glucuronides for 5-F-DALT, one N-deallyl hydroxy-aryl, the carboxy, and one dihydroxy-aryl metabolite for 7-Me-DALT, and the demethylenyl metabolite, its oxo metabolite, and glucuronide for 5,6-MD-DALT.
... Different N-substitutions also influenced in vivo potency (Nichols et al., 2015;Repke et al., 1985). The pharmacological profiles of many tryptamines have been studied previously at selected targets (Blough et al., 2014;Gatch et al., 2011;McKenna et al., 1990;Nichols et al., 2015;Repke et al., 1985;Shulgin and Carter, 1980), and new and pharmacologically unknown tryptamine derivatives are constantly emerging on the illicit drug market (Araujo et al., 2015;Corkery et al., 2012;EMCDDA, 2014;Greene, 2013;Helander et al., 2014;Tittarelli et al., 2015). Because small changes in molecular structure can alter the pharmacology of these novel designer drugs, studying the in vitro receptor interaction profiles of these novel substances is important. ...
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Background: Phenethylamines are a class of chemicals that includes many psychoactive substances, of which many have become popular recreational drugs with a variety of possible effects, e.g. stimulant, empathogenic, or hallucinogenic. Novel phenethylamines constantly emerge on the illicit drug market and are often sold as “legal highs” over the Internet as alternative to illegal psychoactive drugs. The investigation of the pharmacology of newly emerged phenethylamines is needed for a better understanding of the effects and possible harms of these substances. Objective: We investigated the in vitro pharmacological mechanism of action of the novel phenethylamine derivatives 5-(2-aminopropyl)indole (5-IT), 3,4-dimethylmethcathinone (3,4-DMMC), 4-methylamphetamine (4-MA), 3-methylmethcathinone (3-MMC), and N-methyl-2-aminoindane (N-methyl-2-AI). 5-IT is a positional isomer of the tryptamine drug α-methyltryptamine (αMT) and has previously been confirmed in patients with severe toxicity and in fatal cases [1]. 4-MA was involved in a series of fatalities across Europe [2]. 3,4-DMMC and 3-MMC are structurally closely related to the popular substance mephedrone (4-MMC) and N-methyl-2-AI is a rigid analogue of methamphetamine. Methods: We assessed the inhibition of monoamine transporters for norepinephrine (NET), dopamine (DAT), and serotonin (SERT) in human embryonic kidney (HEK) 293 cells stably expressing the human NET, DAT, or SERT. We treated the cells with various concentrations of the test substances and vehicle control before adding 3H-labeled NE, DA, or 5-HT to initiate uptake transport. We then separated the cells from the uptake buffer by centrifugation through silicone oil. Thereafter, we froze the samples in liquid nitrogen and cut them through the oil phase. We then quantified monoamine uptake by liquid scintillation counting. We fit the uptake data to sigmoidal dose¬–response curves, and determined IC50 values. To assess monoamine release, we preloaded the NET, DAT, or SERT expressing HEK 293 cells with respective neurotransmitter before adding the test substances to initiate monoamine release. Monoamine release was compared with vehicle controls using ANOVA followed by Dunnett’s tests. In addition, we assessed binding affinities to monoamine receptors using HEK 293 cell membranes expressing the respective human receptors. Results: All novel phenethylamine derivatives most potently inhibited the NET. 3,4-DMMC and 4-MA inhibited the SERT more potently than the DAT while 5-IT, 3-MMC, and N-methyl-2-AI inhibited the DAT slightly more potently than the SERT. All drugs caused monoamine release. Additionally, 5-IT exhibited high affinity for the 5-HT2A receptor and N-methyl-2-AI exhibited strong binding to the α2A receptor. Conclusion: All substances strongly inhibited the NET, as it is known for classic amphetamines, suggesting marked sympathomimetic properties. 3,4-DMMC and 4-MA inhibited the SERT more strongly than the DAT exhibiting pharmacological properties similar to 3,4-methylenedioxymethamphetamine (MDMA) and suggesting similar empathogenic effects. 5-IT is structurally closely related to the tryptamine hallucinogens and its strong stimulation of the 5-HT2A receptor likely results in hallucinogen-like properties as well.
... Different N-substitutions also influenced in vivo potency (Nichols et al., 2015;Repke et al., 1985). The pharmacological profiles of many tryptamines have been studied previously at selected targets (Blough et al., 2014;Gatch et al., 2011;McKenna et al., 1990;Nichols et al., 2015;Repke et al., 1985;Shulgin and Carter, 1980), and new and pharmacologically unknown tryptamine derivatives are constantly emerging on the illicit drug market (Araujo et al., 2015;Corkery et al., 2012;EMCDDA, 2014;Greene, 2013;Helander et al., 2014;Tittarelli et al., 2015). Because small changes in molecular structure can alter the pharmacology of these novel designer drugs, studying the in vitro receptor interaction profiles of these novel substances is important. ...
Article
The present study investigated interactions between the novel psychoactive tryptamines DiPT, 4-OH-DiPT, 4-OH-MET, 5-MeO-AMT, and 5-MeO-MiPT at monoamine receptors and transporters compared with the classic hallucinogens lysergic acid diethylamide (LSD), psilocin, N,N-dimethyltryptamine (DMT), and mescaline. We investigated binding affinities at human monoamine receptors and determined functional serotonin (5-hydroxytryptamine [5-HT]) 5-HT2A and 5-HT2B receptor activation. Binding at and the inhibition of human monoamine uptake transporters and transporter-mediated monoamine release were also determined. All of the novel tryptamines interacted with 5-HT2A receptors and were partial or full 5-HT2A agonists. Binding affinity to the 5-HT2A receptor was lower for all of the tryptamines, including psilocin and DMT, compared with LSD and correlated with the reported psychoactive doses in humans. Several tryptamines, including psilocin, DMT, DiPT, 4-OH-DiPT, and 4-OH-MET, interacted with the serotonin transporter and partially the norepinephrine transporter, similar to 3,4-methylenedioxymethamphetamine but in contrast to LSD and mescaline. LSD but not the tryptamines interacted with adrenergic and dopaminergic receptors. In conclusion, the receptor interaction profiles of the tryptamines predict hallucinogenic effects that are similar to classic serotonergic hallucinogens but also MDMA-like psychoactive properties.
... I vanlige rusdoser er den akutte toksisiteten lav, men fra andre land er det likevel rapportert om flere dødsfall. Disse tilskrives ikke bare stoffenes toksiske effekter, men også de hallusinogene egenskapene, som kan føre til fatale ulykker (15). ...
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There has been a significant increase in the number of new intoxicants on the illegal drugs market globally, also in Norway. The substances are given the name NPS: Novel Psychoactive Substances, and are mainly sold over the Internet. Uncertain dosage of potent substances entails a risk of accidental overdose, and therefore serious intoxication and death. In this article we provide an overview of current knowledge with regard to these substances.
Chapter
New designer drugs, access to databases, and changing availability of samples for analysis have changed the face of modern forensic toxicology in recent years. Forensic Toxicology: Drug Use and Misuse brings together the latest information direct from experts in each sub-field of the discipline providing a broad overview of current thinking and the most innovative approaches to case studies. The text begins with an in-depth discussion of pharmaco­epidemiology, including information on the value of nationwide databases in forensic toxicology. The use and abuse of drugs in driving, sport and the workplace are then discussed by industry experts who are conducting case work in their field. Not only are new drug groups discussed (NPS), but also their constantly changing impact on drug legislation. Synthetic cannabinoids, khat and mephodrone are discussed in detail. Following a section devoted to legislation and defence, readers will find comprehensive chapters covering sample choice reflecting the increasing use of hair and oral fluid, and also the less commonly used sweat and nail analysis. New and old case examples are compared and contrasted in the final part of the book, which will enable readers to understand how drugs impact on each other and how the interpretative outcome of a case are dependent on many aspects. From use of pharmaceutical drugs in a clinical setting, through smart drugs to new psychoactive drugs, this book documents the wide range in which drugs today are abused. This book will be an essential resource for postgraduate students in forensic toxicology, and for researchers in forensic toxicology laboratories who need the latest data and knowledge.
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New psychoactive substances (NPS) are a group of compounds that mimic the effects of illicit substances. A range of NPS have been shown to interact with the three main classes of monoamine transporters (DAT, NET, and SERT) to differing extents, but it is unclear why these differences arise. To aid in understanding the differences in affinity between the classes of monoamine transporters, several in silico experiments were conducted. Docking experiments showed there was no direct correlation between a range of scoring functions and experimental activity, but Spearman ranking analysis showed a significant correlation (α = 0.1) for DAT, with the affinity ΔG (0.42), αHB (0.40), GoldScore (0.40), and PLP (0.41) scoring functions, and for DAT (0.38) and SERT (0.40) using a consensus scoring approach. Qualitative structure-activity relationship (QSAR) experiments resulted in the generation of robust and predictive three-descriptor models for SERT (r 2 = 0.87, q 2 = 0.8, and test set r 2 = 0.74) and DAT (r 2 = 0.68, q 2 = 0.51, test set r 2 = 0.63). Both QSAR models described similar characteristics for binding, i.e., rigid hydrophobic molecules with a biogenic amine moiety, and were not sufficient to facilitate a deeper understanding of differences in affinity between the monoamine transporters. This contextualizes the observed promiscuity for NPS between the isoforms and highlights the difficulty in the design and development of compounds that are isoform-selective.
Article
There are global concerns about the proliferation and misuse of club drugs and novel psychoactive substances, yet we know little about their harms and research on clinical management and treatment remains limited. This book fills the knowledge gap by providing a detailed overview of the research evidence available to date. The book provides a framework that allows readers to understand this large number of new drugs, using classifications based on primary psychoactive effect. Within this framework, the book provides detailed reviews of the more commonly used drugs. Each chapter explores pharmacology, patterns and mode of use, acute and chronic harms, and clinical interventions supported by research evidence. An invaluable resource for clinical staff, this book will support clinicians working in the emergency department, substance misuse and addiction services, mental health services, primary care, sexual health services and more. It will also be of interest to academics and those developing drug policy.
Article
Aims Understand the metabolic behavior of new psychoactive substances furanylfentanyl, TFMPP, and 5-MeO-DALT. Background New psychoactive substances (NPS) are associated with a number of health and social harms on both the individual and societal levels. Many of them are not regulated and have become increasingly popular among drug users around the world. The lack of clinical studies on the effects and toxicity of these drugs has made the interpretation of their toxicological symptoms difficult. Objective Perform an in vitro metabolism study of new psychoactive substances furanylfentanyl, TFMPP, and 5-MeO-DALT, reveal their possible metabolites and metabolic pathways in human liver microsome. Method A regular human liver microsomal system was used to investigate the potential biotransformation of furanylfentanyl, TFMPP, and 5-MeO-DALT in vitro, and a high resolution mass spectrometry (LC-Q/TOF-MS) was used to perform metabolite detection and identification. Result The three components were substantially metabolized in 4 hours with varied metabolic pathways, and most of the metabolites were generated through phase I metabolic reactions. Furanylfentanyl underwent the metabolic pathways of epoxidation and hydration, furanyl ring opening and oxidation, hydroxylation, hydrolysis of the amide group, and N-dealkylation; TFMPP underwent the metabolic pathways of hydroxylation, and the successive piperazidine ring scission; while 5-MeO-DALT underwent the metabolic pathways of O-demethylation and glucuronidation, dihydroxylation, hydroxylation, oxidation, O-demethylation, N-dealkylation and methylation and N-dealkylation. Conclusion Our data would contribute to a better understanding of furanylfentanyl, TFMPP, and 5-MeO-DALT in their in vitro metabolism study, which was beneficial to predict their metabolic behavior in vivo, and promote their drug monitoring in both clinically used and socially/illegally abused.
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This study aims to determine prevalence and frequency of use of novel psychoactive substances (NPS) and to identify the factors associated with NPS use in an Italian sample of patients diagnosed with substance use disorder (SUD). Prevalence and correlates of NPS knowledge and use were assessed in 185 patients with SUD in three addiction services (Padova, Belluno, Feltre) in the Veneto region with an ad-hoc designed survey. Two thirds of the samples reported knowing NPS and one third reported using them. NPS were considered by them less dangerous than “regular” substances of abuse (t = 6.06 mean 0.78, p < 0.001). Factors associated with NPS use were youth (OR = 4.81; p < 0.001), studentship (OR = 4.99; p = 0.004), subsequent mental disorders diagnosis (OR = 2.49; p = 0.027), suicide attempt history (OR = 11.67; p < 0.001), home detention (OR = 2.30; p = 0.040), residential care (OR = 5.66; p = 0.002), and polysubstance abuse (t = 8.99 mean 2.65 p < 0.001). NPS use in patients with SUD is highly prevalent, particularly in the youngest age group, and associated with psychiatric comorbidity and worse prognosis. It is crucial to systematically assess NPS use and inform addiction service users with SUD of the toxic and potentially lethal side effects. Mental healthcare professionals working in addiction services should receive education and training. Cohort and longitudinal studies are needed.
Chapter
This chapter describes the pharmacology, clinical effects and toxicology of naturally occurring tryptamines (including dimethyltryptamine and mitragynine), and synthetic tryptamines (unsubstituted, 4-substituted and 5-substituted). A description of the diverse pharmacokinetic properties of tryptamines is followed by a review of receptor interactions, particularly serotonin receptor agonism responsible for hallucinogenic psychoactive effects. User reports detailing desired effects of tryptamines are reviewed. The chapter describes prevalence data demonstrating increasing use of synthetic tryptamines in the developed world, and the use of naturally occurring tryptamines including mitragynine outside of traditional settings. Animal and human experimental data demonstrating tryptamine toxicity is reviewed, followed by a summary of user reports describing unwanted effects. The chapter concludes by reviewing deaths associated with tryptamine exposure including deaths associated with the increasing use of mitragynine.
Chapter
The drugs of abuse market has been steadily increasing, and new classes of psychoactive substances appear every year, with potential addictive properties and side effects. Healthcare providers need to be aware of the toxicodynamic and toxicokinetic properties of these drugs for prevention, diagnosis and treatment of emergency cases. Serotonergic hallucinogens or psychedelics are strong psychoactive substances that act on the psychological state and influence the mood and several other processes in the brain. Among these, the use of the psychoactive natural substances has a long history in many cultures in sacred and religious rituals. Starting from the 1960s and 1970s, their popularity increased also as drugs of abuse. Serotoninergic hallucinogens include the classical psychedelic natural products containing N,N-dimethyltryptamine, psilocybin and psilocin, bufotenine, mescaline, lysergic acid amide, the synthetic hallucinogens as lysergic acid diethylamide, and the new hallucinogenic substances as tryptamine and phenethylamines derivatives, for which little is known regarding the toxicological properties and acute and chronic effects. This chapter provides a comprehensive update on serotoninergic hallucinogens, starting from their history and focusing on their classification, toxicokinetics, toxicodynamics, acute and chronic effects. https://www.sciencedirect.com/science/article/pii/B9780323852159000222 Preface Toxicology is a multidisciplinary science where a vast interdisciplinary field of applications is continuously evolving and developing, aiming to maintain and enhance the safety of global health and to assist and strengthen ongoing policy regulatory frameworks. Thinking outside the box, the concept of toxicology has successfully evolved throughout the years, as new research techniques have been developed on preexisting methods and new data became available, resulting in a continuous update of our current knowledge on many different toxicological aspects. The development, improvement, and validation of such steps significantly improve our ability to further understand the hazards and risks posed by chemicals and toxic stimuli that are detrimental to human health. In modern life today, simultaneously or sequentially, we are all exposed to chemicals from diverse sources where a toxicological risk assessment has played a pivotal role in clarifying the mechanistic reasons and resulting outcomes. This book focuses on crucial modern toxicology issues highlighting aspects such as toxicity methods and models, testing tools and concepts, risk-assessment insights, pharmaceuticals and nutraceuticals, biomaterials and nanomaterials, special topics in toxicology, epidemiology, and public health, and clinical biomarkers, among others, providing an “in-depth” review of today’s scientific stance, equally benefiting toxicological scientific communities and respective regulatory bodies. Written by renowned and leading experts in these scientific fields with whom I have been closely collaborating over the past decade, this resource is dedicated to all toxicological risk assessments and multihealth impacts from different exposures. I am immensely proud of this collection of excellent studies and strongly believe that it will be a valuable asset to all scientists working on risk assessment and a substantial contribution to modern toxicology. The book’s success belongs to the authors of the chapters. The design of the book is based on the expertise and knowledge of many collaborations and partners in research. Of course, there will always be room for improvement, but the book provides an attempt at a holistic approach. The central philosophy is, “we know less than we think we know” (Socrates).
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The world market for food supplements is large and is driven by the claims of these products to, for example, treat obesity, increase focus and alertness, decrease appetite, decrease the need for sleep or reduce impulsivity. The use of illegal compounds in food supplements is a continuous threat, certainly because these compounds and products have not been tested for safety by competent authorities. It is therefore of the utmost importance for the competent authorities to know when new products are being marketed and to warn users against potential health risks. In this study we present an approach to detect new and unknown stimulants in food supplements using machine learning. More than 20 new stimulants were identified from two different data sources, namely scientific literature applying word embedding on > 2 million abstracts and articles from formal and social media on the world wide web using text mining. The results show that the developed approach may be suitable to detect “unknowns” in the emerging risk identification activities performed by the competent authorities, which is currently a major hurdle.
Article
Psychedelics alter the perception of reality through agonist or partial agonist interaction with the 2A serotoninergic receptor. They are classified as phenethylamines, tryptamines and lysergamides. These classes, according to the United Nations Office on Drugs and Crime (UNODC) and European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), account for an important percentage of the new psychoactive substances (NPS) current scenario.The paper aimed at: a) identifying and categorising psychedelic molecules from a list of psychonaut websites and NPS online resources; and b) comparing the NPSfinderⓇ results with those from the European and United Nations databases. A crawling software (i.e. ‘NPSfinderⓇ’) was created to automatically scan, 24/7, a list of URLs and to extract a range of information (chemical/street names, chemical formulae, etc.) to facilitate NPS identification. Data collected were manually analysed and compared with the EMCDDA and UNODC databases.The overall number of psychedelic NPS detected by NPSfinderⓇ (November 2017-February 2020) was 1344, almost ten-times higher than that reported by the UNODC and EMCDDA combined. Of these, 994 previously unknown molecules were identified as (potential) novel psychedelics, suggesting a strong discrepancy between online and real-world NPS scenarios. The results show the interest of psychonauts, and maybe of the much larger community of ‘recreational’ drug users, towards psychedelics. Moreover, examining online scenario may help in assessing the availability in the real world of psychedelic NPS; understanding drug trends; and in possibly predicting future drug scenarios
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The title compound, bis­(N,N-diallyl-5-meth­oxy­tryptammonium) (5-MeO-DALT) fumarate (systematic name: bis­{N-[2-(5-meth­oxy-1H-indol-3-yl)eth­yl]- N-(prop-2-en-1-yl)prop-2-en-1-aminium} (E)-but-2-enedioate), 2C17H23N2O⁺·C4H2O4²⁻, has a single tryptammonium cation and half of a fumarate dianion in the asymmetric unit. The tryptammonium and fumarate ions are held together in one-dimensional chains by a series of N—H⋯O hydrogen bonds. These chains are combinations of R⁴4(22) rings, and C²2(14) and C⁴4(28) parallel chains along [111].
Article
Tryptamines are hallucinogenic substances many of which have appeared recently as novel psychoactive substances (NPS). Herein, we describe the establishment of a rapid UHPLC-MS/MS quantitative method for the targeted screening of 16 tryptamines of abuse in hair. Twenty milligram pieces of hair were pulverized below 4 °C in 0.5 mL of deionized water containing 0.1% formic acid and an internal standard (2 ng/mL psilocin-d10 and psilocybin-d4). After subsequent centrifugation, 5 μL of the supernatant was injected into a LC-MS/MS system fitted with a Waters Acquity UPLC HSS T3 column (100 mm × 2.1 mm, 1.8 μm). The column was gradient eluted at 0.3 mL/min with mobile phases composed of 20 mmol/L ammonium acetate, 5% acetonitrile, and 0.1% formic acid in water (solvent A) and acetonitrile (solvent B). Limits of detection ranged between 0.1 and 20 pg/mg, with limits of quantitation ranging from 3 to 50 pg/mg. The calibration curves for all analytes were linear (r > 0.992). Accuracies varied between 91% and 114%, with intraday precision RSDs < 14% and interday precision RSDs of between 1.3% and 14%. The recoveries of all tryptamines were in the 85-115% range, with the matrix effect ranging from 95% to 112%. The validated method was successfully used to analyse 191 hair samples from suspected tryptamine users, 77 of which were 5-MeO-DiPT-positive, while the 16 tryptamines and their metabolites were not detected in the remaining 114 hair samples. 5-MeO-DiPT and its 5-MeO-NiPT, 5-OH-DiPT, and 4-OH-DiPT metabolites were concurrently detected in 34 hair samples. 5-MeO-DiPT, as the parent drug, was the parent substance found in the hair samples.
Article
An efficient strategy for the synthesis of structurally diverse homotryptamines and allyl amines via a Rh(II)‐catalyzed tandem reaction of 1,2,3‐triazolyl esters with either indoles or 1,3,5‐trimethoxybenzene has been developed. The reaction proceeds via Rh(II)‐catalyzed intramolecular rearrangement of triazoles into 1‐azadienes followed by regioselective nucleophilic addition. The efficiency of the current protocol was illustrated by broad substrate scope, gram scale synthesis and further functionalization of homotryptamines into other biologically relevant heterocycles. magnified image
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The title compound {systematic name: N-[2-(5-meth­oxy-1H-indol-3-yl)eth­yl]-N-(prop-2-en-1-yl)prop-2-en-1-amine), C17H22N2O, has a single tryptamine mol­ecule in the asymmetric unit. The mol­ecules are linked by strong N—H⋯N hydrogen bonds into zigzag chains with graph-set notation C(7) along the [010] direction.
Article
Background: Impurities in commonly used illicit drugs raise concerns for unwitting consumers when pharmacologically active adulterants, especially new psychoactive substances (NPS), are used. This study examines impurities detected in illicit drugs seized in one Australian jurisdiction. Methods: Queensland Health Forensic and Scientific Services provided analytical data. Data described the chemical composition of 9346 samples of 11 illicit drugs seized by police during 2015-2016. Impurities present in primary drugs were summarized and tabulated. A systematic search for published evidence reporting similar analyses was conducted. Results: Methamphetamine was the primary drug in 6608 samples, followed by MDMA (1232 samples) and cocaine (516 samples). Purity of primary drugs ranged from ∼30% for cocaine, 2-CB and GHB to >90% for THC, methamphetamine, heroin and MDMA. Methamphetamine and MDMA contained the largest variety of impurities: 22 and 18 variants, respectively. Drug adulteration patterns were broadly similar to those found elsewhere, including NPS, but in some primary drugs impurities were found which had not been reported elsewhere. Psychostimulants were adulterated with each other. Levamisole was a common impurity in cocaine. Psychedelics were adulterated with methamphetamine and NPS. Opioids were quite pure, but some samples contained methamphetamine and synthetic opioids. Conclusions: Impurities detected were mostly pharmacologically active adulterants probably added to enhance desired effects or for active bulking. Given the designer nature of these drug cocktails, the effects of the adulterated drugs on users from possible complex multi-drug interactions is unpredictable. Awareness-raising among users, research into complex multi-drug effects and ongoing monitoring is required.
Article
Several novel psychoactive substances have emerged in recent years. Users are typically young men who use other substances. In the category of stimulants, cathinones ("bath salts") have predominated and can lead to agitation, psychosis, hyperthermia, and death. Synthetic cannabinoids ("spice") are more potent than marijuana and can lead to agitation, psychosis, seizures, and death. There are no rapid tests to identify these substances and general treatment includes benzodiazepines for agitation and supportive therapy. Many Synthetic opioids are potent analogues of fentanyl and carry a high risk of overdose. In addition, there are several designer benzodiazepines that have emerged.
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Fundamentación: nuevas sustancias y nuevas formas de consumo emergen en el mercado de las drogas. Internet desempeña un papel esencial en la distribución fácil y anónima de éstas, así como en la cultura del consumo. Muchas de estas drogas escapan a la legislación, pues son novedosas o están originalmente destinadas a otros usos. Objetivos: obtener una visión global y actual sobre las drogas emergentes más relevantes, por su popularidad o su potencial peligro para la salud. Metodología: revisión bibliográfica de trabajos publicados en la literatura científica, sobre algunas de las drogas emergentes más populares o más peligrosas para la salud, así como de blogs y páginas web no indexadas científicamente. Resultados: los cannabinoides sintéticos son una de las drogas con más auge y suponen una alternativa legal al cannabis. Algunas sustancias de origen vegetal (kratom, estramonio, belladona) se consumen por su efecto psicotropo. La mefedrona es la droga que más muertes concita. El bromo-DragonFLY también se ha asociado a desenlaces fatales. Conclusiones: resulta prioritario atender estas cuestiones, puesto que es cada vez más frecuente el reporte de casos en la literatura médica, a la vez que son desconocidos los riesgos a medio y largo plazo.
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Background Although illegal drug use has largely been declining in the UK over the past decade, this period has witnessed the emergence of a range of novel psychoactive substances (NPS) (‘legal highs’). These are new, mostly synthetic, substances that mimic the effects of existing drugs). Despite there being many causes for concern in relation to NPS, there has been little prior study of the burden associated with their use in public health terms. Clarity is lacking on research priorities in this rapidly developing literature. Objectives To inform the development of public health intervention research on NPS by reviewing existing data on their use, associated problems and potential responses to such problems. Design A scoping review and narrative synthesis of selected bodies of evidence was undertaken to summarise and evaluate what is known about NPS use and the related harms of, and responses to, such use. Relevant literature was identified from electronic databases (covering January 2006 to June 2016 inclusive), Google (Google Inc., Mountain View, CA, USA), relevant websites and online drug forums and by contacting experts. Articles were included if they were primary studies, secondary studies involving the analysis and interpretation of primary research or discussion papers. A conceptual framework postulating an evidence-informed public health approach to NPS use in the UK was developed through a pragmatic literature review, the iterative development of concepts and finalisation in light of the results from the empirical review work. The process also involved feedback from various stakeholders. Research recommendations were developed from both strands of work. Results A total of 995 articles were included in the scoping review, the majority of which related to individual-level health-related adverse effects attributable to NPS use. The prevalence of lifetime NPS use varied widely between (e.g. with higher prevalence in young males) and within population subgroups. The most commonly reported adverse effects were psychiatric/other neurological, cardiovascular, renal and gastrointestinal manifestations, and there is limited evidence available on responses. In these and other respects, available evidence is at an early stage of development. Initial evidence challenges the view that NPS should be treated differently from other illicit drugs. The conceptual framework indicated that much of the evidence that would be useful to inform public health responses does not yet exist. We propose a systems-based prevention approach that develops existing responses, is multilevel and life course informed in character, and emphasises commonalities between NPS and other legal and illegal drug use. We make 20 recommendations for research, including nine key recommendations. Limitations Scoping reviews do not interrogate evidence in depth, and the disjunction between the scoping review and the conceptual framework findings is worthy of careful attention. Conclusions Key research recommendations build on those that have previously been made and offer more evidence-based justification and detail, as previous recommendations have not yet been acted on. The case for decision-making on commissioning new research based on these recommendations is both strong and urgent. Future work The validity of recommendations generated through this project could be enhanced via further work with research commissioners, policy-makers, researchers and the public. Study registration The systematic review element of this study is registered as PROSPERO CRD42016026415. Funding The National Institute for Health Research Public Health Research programme.
Article
There has been increasing use of novel synthetic hallucinogenic compounds, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25B-NBOMe), 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25C-NBOMe), 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25I-NBOMe), and N,N-diallyl-5-methoxy tryptamine (5-MeO-DALT), which have been associated with severe toxicities. These four compounds were tested for discriminative stimulus effects similar to a prototypical hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) and the entactogen (±)-3,4-methylenedioxymethamphetamine (MDMA). Locomotor activity in mice was tested to obtain dose range and time-course information. 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe decreased locomotor activity. 5-MeO-DALT dose dependently increased locomotor activity, with a peak at 10 mg/kg. A higher dose (25 mg/kg) suppressed activity. 25B-NBOMe fully substituted (≥80%) in both DOM-trained and MDMA-trained rats at 0.5 mg/kg. However, higher doses produced much lower levels of drug-appropriate responding in both DOM-trained and MDMA-trained rats. 25C-NBOMe fully substituted in DOM-trained rats, but produced only 67% drug-appropriate responding in MDMA-trained rats at doses that suppressed responding. 25I-NBOMe produced 74-78% drug-appropriate responding in DOM-trained and MDMA-trained rats at doses that suppressed responding. 5-MeO-DALT fully substituted for DOM, but produced few or no MDMA-like effects. All of the compounds, except 25I-NBOMe, fully substituted for DOM, whereas only 25B-NBOMe fully substituted for MDMA. However, the failure of 25I-NBOMe to fully substitute for either MDMA or DOM was more likely because of its substantial rate-depressant effects than weak discriminative stimulus effects. All of the compounds are likely to attract recreational users for their hallucinogenic properties, but probably of much less interest as substitutes for MDMA. Although no acute adverse effects were observed at the doses tested, the substantial toxicities reported in humans, coupled with the high likelihood for illicit use, suggests that these compounds have the same potential for abuse as other, currently scheduled compounds.
Article
For the last 10 years, recreational use of new psychoactive substances (NPS) with hallucinogenic properties was more and more described either in a context of consumption during a rave-party or at home alone or in small group. A review of 62 cases (56 M, 6 F, 16–46 y) registered from 2011 to 2016 at the French Grand Ouest centre antipoison of Angers is presented. Some of them (n = 15) presented a severe clinical state (poison severity score, PSS = 3) and only one was a fatal intoxication (PSS = 4). Treatment of acute intoxication was mainly based on supportive care with a quick recovery in less than 48 h. A high number of these cases were documented by plasma (pl) and/or urine analyses using LC-UV, GC-MS and LC-MS². Several powders or other forms bought on the web market by the patients were also analysed. Six amphetamines derivates were detected such as methiopropamine (pl: 50 – 430 μg/L, n = 6) or 5 others (6-APB, 6-APDB, 5-EAPB, 5-MAPB, 2-FA each once). Four 2,5-dimethoxy-derivates of phenylethylamines (2Cs) or of amphetamines (DOs) were detected as 2C-P (pl: < 10–20 μg/L, n = 5), 2C-T-4 (88 μg/L) or 2C-E (only in one urine) and DOC (n = 5, pl: < 10–18 μg/L). In 24 cases, 12 different cathinones were observed in plasma samples (n = 8) as MDPV (pl: 10–40 μg/L, n = 4), 3-MMC (pl: 7–300 μg/L, n = 6), 4-MEC (pl: 240 – 890 μg/L, n = 3), mexedrone (pl: 100 and 180 μg/L) and methylone (3130 μg/L in a peripheral post-mortem blood). Others cathinones (4-MMC, α-PVP, 4-chloro-α-PVP, bk-2C-B, MDPP, MPHP, pentedrone) were essentially observed in urine or in powders. Two tryptamine analogs were found as AMT (pl: 440 μg/L in one plasma sample) and 5-MeO-DALT (n = 5). The 3 ketamine-like compounds (n = 17) detected in plasma were methoxetamine (pl: 8.6–360 μg/L, n = 12), methoxphenidine (pl: 254–590 μg/L, n = 3) and diphenidine (pl: 20 μg/L, n = 1). Five other miscelleanous drugs were found in 11 cases and 9 different synthetic cannabinoids (AB-CHMINACA, AB-FUBINACA, AKB48, 5F-AKB48, 5FUB-AKB48, 5F-PB22, AM1220, MDMB-CHMICA, UR-144) were found in 7 different patients. For the same period, illicit amphetamines constituted 52 cases with amphetamine or ecstasy intake sometimes combined with NPS. These data were presented to show the increasing use of wide-range NPS in a French region and to provide quantitative data in clinical situations besides the large information on the post-mortem cases available in the literature.
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A series of indole-ethylamines were tested for their ability to suppress the spontaneous firing of single dorsal raphe serotonergic neurons in the rat. The compounds were all derivatives of either tryptamine or N,N-dimethyltryptamine possessing hydroxy or methoxy substituents on the benzene ring portion of the indole nucleus. Their activity was assessed using quantitative microiontophoresis or following systemic (intravenous) administration. The serotonin autoreceptor or so-called "S2 receptor" mediating the inhibition of raphe serotonergic neurons was found to exhibit a high degree of structural specificity among the closely related tryptamine analogs. The following structure-activity rules were demonstrated: (1) for either hydroxy or methoxy derivatives, the relative favorability of the ring positions conforms to the series 5 much greater than 4 greater than 6; (2) methoxy derivatives are more sensitive to a shift of the ring substituent from the 5- to the 4- or 6-positions than are hydroxy compounds; and (3) activity is enhanced by N,N-dimethylation. Furthermore, addition of a methyl group at the 7-position of 5-methoxy-N,N-dimethyltryptamine markedly reduces the activity of this potent agonist. Of the radioligands which label brain serotonin receptors, the pharmacological characteristics of D-[3H]lysergic acid diethylamide binding best correspond to those displayed by the S2 receptor as determined in the present physiological analysis, although sufficient data are not yet available to make a complete comparison.
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The clinical features are reported in 27 cases of ‘magic mushroom’ ingestion. Mydriasis and hyperreflexia were common as were disorders of perception and affect. Psilocybe semilanceata appears to have been the species of fungus involved.
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In February 2003, the Miami-Dade County Medical Examiner Department reported the first known death in the country related to alpha-methyltryptamine (AMT). AMT is an indole analogue of amphetamine investigated in the 1960s as an antidepressant, stimulant, and monoamine oxidase inhibitor. Today, AMT is recognized as a powerful psychedelic drug among high school and college-aged men and women. Its popularity is partly due to the multitude of anecdotal websites discussing AMT as well as its legality and availability for purchase via the Internet prior to April 2003. Emergency designation of AMT as a Schedule 1 controlled substance by the Drug Enforcement Administration occurred shortly after the death in Miami-Dade County. The case in Miami involved a young college student who, prior to death, advised his roommate that he was "taking hallucinating drugs" and as a result had "discovered the secret of the universe". Approximately 12 h later, the roommate discovered the deceased lying in bed unresponsive. An empty 1-g vial of AMT was recovered from the scene and sent to the toxicology laboratory. Initial screening of urine by enzyme-multiplied immunoassay technique was positive for amphetamines, and the basic drug blood screen detected a small peak later identified by mass spectrometry as AMT. For quantitation, AMT was isolated using solid-phase extraction, derivatized with pentafluoropropionic anhydride, and analyzed using gas chromatography-mass spectrometry. Quantitative analysis was based upon m/z 276, 303, and 466 for AMT and m/z 306, 333, and 496 for the internal standard, 5-methoxy-alpha-methyltryptamine. A linear calibration curve from 50 to 500 ng/mL was used to calculate the concentration of AMT in the samples and controls. Blood, tissue, and gastric specimens were diluted to bring the observed concentration within the limits of the standard curve. Matrix matched controls were extracted and analyzed with each run. Postmortem iliac vein blood revealed 2.0 mg/L, gastric contents (48 g collected at autopsy) contained 9.6 mg total of AMT, liver contained 24.7 mg/kg, and the brain contained 7.8 mg/kg. An additional Medical Examiner case from another jurisdiction revealed 1.5 mg/L in antemortem serum.
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We constructed a reproducible, simple, and small-scale determination method of the psychoactive drugs that acted directly on the monoamine receptor by measuring the activation of [S-35]guanosine-5'-O-(3-thio)-triphosphate binding to guanine nucleotide-binding proteins (G proteins). This method can simultaneously measure the effects of three monoamines, namely dopamine (DA), serotonin (5-HT), and norepinephrine (NE), in rat brain membranes using a 96-well microplate. Activation of D-1 and D-2 receptors in striatal membranes by DA as well as 5-HT and NE alpha(2) receptors in cortical membranes could be measured. Of 12 tested phenethylamines, 2,5-dimethoxy-4-chlorophenethylamine (2C-C), 2,5-dimethoxy-4-ethylphenethylamine (X-E), and 2,5-dimethoxy-4-iodophenethylamine (2C-I) stimulated G protein binding. The other phenethylamines did not affect G protein binding. All 7 tryptamines tested stimulated G protein binding with the following rank order of potency; 5methoxy-N,N-dimethyltryptamine (5-MeO-DMT)> 5-methoxy-NN-diallyltryptamine (5-MeO-DALT)> 5-methoxy-alpha-methyltryptamine (5-MeO-AMT)5-methoxy-N,N-methylisopropyltryptamine (5-MeO-MIPT)> 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT)> N,N-dipropyltryptamine (DPT)>=alpha-methyltryptamine (AMT). This assay system was able to designate psychoactive drugs as prohibited substances in accordance with criteria set forth by the Tokyo Metropolitan government.
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Hallucinogenic tryptamine analogues, an important class of drugs of abuse, can be naturally occurring or chemically synthesized compounds. In Japan, psilocin and psilocybin (ingredients of “magic mushrooms”) and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT; a synthetic tryptamine) seem to be particularly problematic due to their extensive abuse. This review is focused on human metabolism and forensic toxicological analyses of the above three tryptamine analogues. In humans, psilocybin is rapidly dephosphorylated to form psilocin, and most of the psilocin is eventually conjugated to form its glucuronide. On the other hand, 5-MeO-DIPT is mainly metabolized via O-demethylation, 6-hydroxylation, and N-deisopropylation, partly followed by conjugation to form their sulfates and glucuronides. Suitable hydrolysis should be, therefore, applied for sensitive and effective analysis of the metabolites. In analyzing psilocin and psilocybin by gas chromatography-mass spectrometry (GC-MS), derivatization is necessary for their discriminative identification. Although 5-MeO-DIPT and its three major metabolites can be analyzed by GC-MS without any derivatization, trimethylsilyl derivatization provides improvement of their peak shapes and intensities. In contrast to GC-MS, liquid chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry allow us not only to discriminate psilocin and psilocybin without derivatization, but also to directly analyze their conjugated metabolites.
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'Legal highs' are psychoactive chemicals which are sold from 'head shops', the internet and from street suppliers and may be possessed without legal restriction. An increase in the marketing of these materials has resulted in a corresponding increase in published reports of their adverse effects. However, a lack of primary literature pertaining to their chemistry, pharmacology and toxicology, makes an evaluation of their harm difficult. This review covers the basic chemistry of these novel psychoactive compounds and relates them to endogenous neurotransmitters and existing drugs of abuse. A survey of the internet was used to identify websites that are marketing 'legal highs' in the UK. Trivial and systematic chemical compound names, for example methoxetamine, 4-methoxyphencycline, 4-fluorotropacocaine and ethyl phenidate were entered into PubMed to retrieve data on these compounds. This search elicited no citations. Other search terms which were more fruitful included desoxypipradrol, diphenylprolinol, methylenedioxy-2-amino-indane and methylenedioxy-2-amino-tetralin, alpha-methyltryptamine and 5-methoxy-N,N-diallyl-tryptamine. 'Legal highs' from the phenylethylamine, cocaine, tryptamine and phencyclidine classes are increasingly being marketed and, in the majority of cases, little is cited in the literature on their true chemical identity, pharmacology or toxicology. 'Legal highs' are gaining in popularity and present clear challenges to toxicologists and society as a whole. Whilst improved use of existing legislation and development of new legislation can be used to reduce the supply of these materials, investment in better education for young people on the harms associated with 'legal highs' is needed.
Article
The aim of the present study was to answer the question whether amines other than 5-hydroxytryptamine (5-HT) and tryptamine act as substrates of the platelet 5-HT transporter. To this end, a large number of tryptamines, 5-HT receptor agonists and phenethylamines (which had IC50 values for 3H-5-HT uptake inhibition of 145-24,500 nmol l-1) was examined in rabbit platelets in order to determine their ability to induce an outward transport of 3H-5-HT. Platelets (the MAO of which was blocked) from reserpine-pretreated animals were loaded with 3H-5-HT and then exposed for 5 min to various concentrations (ranging from 0.25 to 40 times the IC50) of each compound. The concentration-effect curves for the drug-induced increase in 3H-5-HT efflux served to determine values of Emax (maximum increase in efflux expressed in % of the 3H-5-HT content of cells) and EC50 (drug concentration producing Emax/2). For the 24 compounds studied here (which included the 5-HT uptake inhibitors imipramine, citalopram, fluoxetine and cocaine) a linear correlation between EC50 and IC50 (r = 0.975) and a mean ratio of EC50/IC50 of 2.4 was found. Most of the compounds +ADe.g., (+/-)8-hydroxy-2-(N,N-dipropylamino)tetralin, S(+)alpha-methyl-5-HT, 5-carboxamidotryptamine and 5-methoxytryptamine+BD gave rise to Emax values (15.8-32.5%) that exceeded that brought about by imipramine (6.6%), indicating that they act as substrates of the 5-HT transporter; the 3H-5-HT outward transport observed in response to these substances was abolished in the presence of imipramine.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The selective monoamine oxidase inhibitors clorgyline and (-)-deprenyl have been used to determine the activities of monoamine oxidase-A and -B towards tryptamine in several human tissues. The results were compared with those obtained with the A-form-selective substrate 5-hydroxytryptamine, the B-form-selective substrate 2-phenethylamine and the common substrate tyramine. Tryptamine was found to be a substrate for both forms of the enzyme in human liver, kidney cortex and medulla and in seven different brain regions. The Km values of the two forms towards this substrate were similar in all the human tissues examined but the maximum velocities differed. Thus the A-form would contribute approximately 50% of the total monoamine oxidase activity towards this substrate in human cerebral cortex, whereas it would contribute about 60% in kidney cortex and medulla and 75% in liver. These results suggest that both forms of monoamine oxidase would contribute to the metabolism of tryptamine in human tissues and are difficult to reconcile with suggestions that tryptamine excretion may provide a simple index of monoamine oxidase-A inhibition.
Article
Tryptamine synthesized by decarboxylation of L-tryptophan occurs as an endogenous constituent of mammalian brain albeit at very low concentrations (low ng/g range). It is primarily metabolized by oxidative deamination by MAO and possesses an extremely rapid turnover and half-life. Subcellular localization appears to be in nerve terminals and it is releasable by electrical or potassium evoked depolarization. Neuropharmacological and electrophysiological data strongly suggest the existence of post-synaptic receptors for tryptamine independent of those for 5HT. There may exist a rostrally projecting neuronal tryptamine containing system arising from cell bodies in or close to the nucleus raphé medianus. The demonstration of specific receptors for tryptamine in the CNS strongly indicates a transmitter role, although a strong case can be made for a role as a modifier of central 5HT systems. The possibility also exists that 5HT and tryptamine may be mediators of functionally opposite neuronal pathways. Whatever the role of tryptamine in the CNS it is clear that it not simply present as an accident of metabolism or a "biological artefact." The indications are that it possesses important functions in central neurotransmission.
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The discovery of enhancer regulation in the mesencephalon and the concept that it plays a key role in the operation of innate and acquired drives [Neurochem. Res. 28 (2003) 1187] sets the trace amines (TAs) in their true physiological perspective. The regulation is defined as the existence of enhancer-sensitive neurons in the brain capable of working in a split-second on a high activity level due to endogenous enhancer substances. For the time being, only beta-phenylethylamine (PEA) and tryptamine are the experimentally analyzed examples. (-)-Deprenyl (selegiline), widely used in Parkinson's disease and Alzheimer's disease today, and known as the first selective monoamine oxidase (MAO) type-B inhibitor for decades, was identified as a PEA-derived synthetic mesencephalic enhancer substance. An important and convincing confirmation of the enhancer concept was the recent development of a highly specific and potent tryptamine-derived synthetic mesencephalic enhancer substance, (-)-1-(benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP]. This substance, which is specific and hundreds of times more potent than selegiline, is now the best experimental tool to study the enhancer regulation in the mesencephalon and a promising candidate to significantly surpass the therapeutic efficiency of selegiline in depression, Parkinson's disease, and Alzheimer's disease.
Article
Foxy is the colloquial name for the hallucinogen 5-ethoxy-diisopropyltryptamine (5-MeO-DIPT). A non-fatality involving a 23-year-old Caucasian man who ingested a capsule containing 5-MeO-DIPT is described. He presented to the Emergency Department, not with visual nor auditory hallucinations but with sensory hallucinations, that of formication and paranoia. He was observed and given supportive care for 4 h, then discharged without any known sequelae. Blood and urine were collected for laboratory analyses. Foxy and its metabolites were identified in urine by gas chromatography-mass spectrometry. The concentrations of 5-MeO-DIPT in the serum and urine were 0.14 and 1.6 microg/mL, respectively. The drug undergoes oxidative deamination to form 5-methoxy-indole acetic acid. The urinary concentration of this metabolite was 0.17 microg/mL. Also, the urine contained three other related compounds. Two of them have been described in a previous case of 5-MeO-DIPT ingestion as 5-methoxy-isopropyltryptamine (5-MeO-IPT) and 5-methoxy-diisopropyltryptamine-N'-oxide (5-MeO-DIPT-N'-oxide). The third compound was substantially present in the urine and was tentatively identified as 5-hydroxy-diisopropyltryptamine (5-OH-DIPT). Only the parent drug, 5-MeO-DIPT was detected in the serum sample.
Article
Hallucinogens (psychedelics) are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They are considered physiologically safe and do not produce dependence or addiction. Their origin predates written history, and they were employed by early cultures in a variety of sociocultural and ritual contexts. In the 1950s, after the virtually contemporaneous discovery of both serotonin (5-HT) and lysergic acid diethylamide (LSD-25), early brain research focused intensely on the possibility that LSD or other hallucinogens had a serotonergic basis of action and reinforced the idea that 5-HT was an important neurotransmitter in brain. These ideas were eventually proven, and today it is believed that hallucinogens stimulate 5-HT(2A) receptors, especially those expressed on neocortical pyramidal cells. Activation of 5-HT(2A) receptors also leads to increased cortical glutamate levels presumably by a presynaptic receptor-mediated release from thalamic afferents. These findings have led to comparisons of the effects of classical hallucinogens with certain aspects of acute psychosis and to a focus on thalamocortical interactions as key to understanding both the action of these substances and the neuroanatomical sites involved in altered states of consciousness (ASC). In vivo brain imaging in humans using [(18)F]fluorodeoxyglucose has shown that hallucinogens increase prefrontal cortical metabolism, and correlations have been developed between activity in specific brain areas and psychological elements of the ASC produced by hallucinogens. The 5-HT(2A) receptor clearly plays an essential role in cognitive processing, including working memory, and ligands for this receptor may be extremely useful tools for future cognitive neuroscience research. In addition, it appears entirely possible that utility may still emerge for the use of hallucinogens in treating alcoholism, substance abuse, and certain psychiatric disorders.
Article
A fatal overdose involving case by 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIFT) is reported. 5-MeO-DIPT and its two metabolites, 5-hydroxy-N,N-diisopropyltryptamine (5-OH-DIPT) and 5-methoxy-N-isopropyltryptamine (5-MeO-NIFT), were identified by LC-MS. The level of 5-MeO-DIPT, 5-OH-DIPT and 5-MeO-NIPT in blood and urine was 0.412,0327 and 0.020 mu g/ml, and 1.67, 27.0 and 0.32 mu g/ml, respectively. These blood and urine levels were higher than published data for such poisoning. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
Article
Only a few formal assessments of websites with drug-related contents have been carried out. We aimed here at fostering collection and analysis of data from web pages related to information on consumption, manufacture and sales of psychoactive substances. GENERAL METHODS: An 8-language, two-engine, assessment of the information available in a purposeful sample of 1633 unique websites was carried out. A pro-drug and a harm reduction approach were evident, respectively, in 18% and 10% of websites accessed. About 1 in 10 websites offered either psychoactive compounds for sale or detailed data on drugs' synthesis/extraction procedures. Information on a number of psychoactive substances and on unusual drugs' combinations not found in the Medline was elicited. This represents the first review which is both comprehensive and multilingual of the online available information on psychoactive compounds. Health professionals may need to be aware of the web being a new drug resource for information and possibly purchase.
Article
Few studies have examined the effects of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) in vivo. In these studies, 5-MeO-DIPT was tested in a drug-elicited head twitch assay in mice where it was compared to the structurally similar hallucinogen N,N-dimethyltryptamine (N,N-DMT) and challenged with the selective serotonin (5-HT)2A antagonist M100907, and in a lysergic acid diethylamide (LSD) discrimination assay in rats where its subjective effects were challenged with M100907 or the 5-HT 1A selective antagonist WAY-100635. Finally, the affinity of 5-MeO-DIPT for three distinct 5-HT receptors was determined in rat brain. 5-MeO-DIPT, but not N,N-DMT, induced the head twitch responses in the mouse, and this effect was potently antagonized by prior administration of M100907. In rats trained with LSD as a discriminative stimulus, there was an intermediate degree (75%) of generalization to 5-MeO-DIPT and a dose-dependent suppression of response rates. These interoceptive effects were abolished by M100907, but were not significantly attenuated by WAY-100635. Finally, 5-MeO-DIPT had micromolar affinity for 5-HT 2A and 5-HT 2C receptors, but much higher affinity for 5-HT 1A receptors. 5-MeO-DIPT is thus effective in two rodent models of 5-HT2 agonist activity, and has affinity at receptors relevant to hallucinogen effects. The effectiveness with which M100907 antagonizes the behavioral actions of this compound, coupled with the lack of significant antagonist effects of WAY-100635, strongly suggests that the 5-HT 2A receptor is an important site of action for 5-MeO-DIPT, despite its apparent in vitro selectivity for the 5-HT 1A receptor.
Article
We developed a reproducible, simple, and small-scale method for determining the re-uptake and release of monoamines (dopamine, serotonin (5-HT) and norepinephrine) using rat brain synaptosomes. These assays were then applied to study the effects of different kinds of non-medically used psychoactive drugs on monoamine re-uptake and release. The phenethylamine derivatives, 4-fluoroamphetamine, 2-methylamino-3,4-methylene-dioxy-propiophenone (methylone), 1-(1,3-benzodioxol-5-yl)-2-butanamine (BDB), and N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB), had strong inhibitory effects on the re-uptake of dopamine, 5-HT and norepinephrine. 4-Fluoroamphetamine, methylone and BDB also strongly increased the release of the three monoamines, but MBDB increased 5-HT and norepinephrine release, but had little effect on dopamine release. However, 2,5-dimethoxy-4-iodophenethylamine (2C-I), 2,5-dimethoxy-4-ethylphenethylamine (2C-E), 2,5-dimethoxy-4-chlorophenethylamine (2C-C), 2,4,5-trimethoxyamphetamine (TMA-2) and 2,4,6-trimethoxyamphetamine (TMA-6), which are methoxylated phenethylamine derivatives, slightly influenced the re-uptake and release of monoamines. Alpha-metyltryptamine (AMT), a tryptamine derivative, was one of the strongest re-uptake inhibitors and releasers of the three monoamines. The tryptamine derivative, 5-methoxy-alpha-methyltryptamine (5-MeO-AMT), also strongly inhibited re-uptake and increased the release of the three monoamines. N,N-dipropyltryptamine (DPT), 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), 5-methoxy-N,N-methylisopropyltryptamine (5-MeO-MIPT), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) inhibited monoamine re-uptake, but had a few effects on monoamine release. 1-(3-Chlorophenyl)piperazine (3CPP) and 1-(methoxyphenyl)piperazine (4MPP), which are piperazine derivatives, inhibited monoamine re-uptake and accelerated their release. The results suggest that some designer drugs strongly act on the central nerve system to the same extent as restricted drugs.
Article
5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a synthetic orally active hallucinogenic tryptamine derivative, known also as Foxy or Foxy methoxy. However, few studies have examined its effects in vitro. In the present study, we investigated the actions of 5-MeO-DIPT against monoamine neurotransmitter transporters, including the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), using COS-7 cells heterologously expressing these transporters and rat brain synaptosomes. 5-MeO-DIPT specifically inhibited the uptake of [3H]serotonin (5-HT) by the SERT-expressing COS-7 cells and rat striatal synaptosomes in a high affinity manner at concentrations similar to those for cocaine. The effect was reversible and competitive. 5-MeO-DIPT failed to stimulate reverse transport of [3H]5-HT through SERT, while it prevented the releasing action of methamphetamine. 5-MeO-DIPT induced cell toxicity at high concentrations in COS-7 cells, and it was not influenced by the expression of SERT. These results demonstrated that 5-MeO-DIPT acts as a competitive SERT inhibitor and has an inability to cause reverse transport, underlying its serotonergic actions.
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What drug is in my drug? Chemical analysis of 5-MeO-DALT and discussion of inconsistent RCs in the 2010 market
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