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research article: Toxicology and Analysis of Psychoactive Tryptamines

#27223652 - 02/24/21 09:55 AM (3 years, 1 month ago)

Toxicology and Analysis of Psychoactive Tryptamines
This article has a very long list of synthetic compounds and toxicity review

MDPI by Sara Malaca et al., December 2020

Only a few sections of the article are pasted in here. The entire article is open access through the link above

Abstract

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.
Keywords: tryptamines; new psychoactive substances (NPS); analytical methods; toxicology; psychedelics

1. Introduction
Psychedelics are a diverse group of naturally occurring and synthetic drugs that induce distorted states of consciousness, perception, thinking and feeling [1]. Tryptamines share their core structure with the neurotransmitter serotonin, also named 5-hydroxytryptamine (5-HT). The effects of psychedelics, including those of tryptamines, are mediated by the 5-HT2A receptor [2,3,4,5,6] but may also be modulated by interactions with other 5-HT receptors, monoamine transporters and trace amine-associated receptors [6,7,8,9,10,11,12,13,14]. Furthermore, Luethi et al. presented a brief report based on correlations between in vitro human 5-HT receptor affinities and their dose estimates [12], reporting that human doses for psychedelics were significantly correlated with 5-HT2A and 5-HT2C receptor binding but not with 5-HT1A receptor binding. 5-HT2A receptors expressed on neocortical pyramidal cells are involved in the psychedelic effects of tryptamines [3]. The activation of 5-HT2A receptors increases cortical glutamate levels by a presynaptic receptor-mediated release from thalamic afferents. As serotonin receptor agonists, psychedelics can produce synesthesia and altered perceptions of reality, where senses usually experienced separately are combined. The status of control for different psychedelics varies, many are controlled under the Convention on Psychotropic Substances of 1971 (e.g., diethyltryptamine (DET), dimethyltryptamine (DMT), α-ethyltryptamine (α-ET)), although some synthetic psychedelics are not currently under international control.

Many countries report the use of psilocybin or magic mushrooms to the United Nations Office on Drugs and Crime (UNODC) [1]. The ranking of drugs by Member States, based on prevalence data from 123 countries, including 78 countries providing psychedelic data, suggests that the use of this drug class is currently ranked on average 5.3 from 2013–2017, being less of a threat than the use of cannabis, sedatives and tranquillizers, opioids and cocaine. From the available data on trends in the use of different substances from 2001–2017, the majority of countries reported no significant change in psychedelic use over time. Nonetheless, there are signs of an increase in the overall use of psychedelics in recent years, particularly from 2012 to 2016, with the number of countries reporting increases in the use of psychedelics greater than the number of countries reporting decreases. Furthermore, according to the 2019 Global Drug Survey (GDS) [15], psychedelics were consumed by 40% of drug users, with tryptamines the psychedelic class with the greatest increase in use. The psychedelics with the greatest prevalence of use were lysergic acid diethylamide (LSD) (17.5%), psilocybin or magic mushrooms (14.8%), DMT (4.2%), magic truffles (3.3%) and ayahuasca (1.1%) [16].
Several tryptamines occur naturally in a variety of plants, fungi and animals [1]. Some tryptamines are also chemically synthesized, with several DMT analogs, such as alpha-methyltryptamine (α-MT) and 5-methoxy-diisopropyltryptamine (5-MeO-DiPT), currently popular.

Several reviews report the toxicology of different NPS [17,18,19,20,21]; however, only two focused on tryptamines [22,23]. In 2015, Tittarelli et al. [22] presented a summary of all the currently available information on tryptamines and their derivatives, including pharmacology, chemical structures and effects related to routes of administration and toxicities. Data were provided for twelve tryptamines and/or derivatives and some intoxication reports. In the same year, Araújo et al. [23] provided an overview for the same classic tryptamines plus other derivatives, providing additional detail on the drugs’ toxicodynamics, preclinical physiological studies and adverse effects in humans. NPS and tryptamines are constantly evolving, with new drugs appearing rapidly onto the market. The morbidity associated with tryptamine intake is considerable and it is important for toxicologists to be informed of the latest data on this public health threat. Our aim is to present the latest tryptamine intoxication cases and new analytical methods to identify and quantify tryptamines in conventional and non-conventional biological matrices over the last five years.

2. Results

Tryptamines are psychedelic drugs derived from decarboxylation of the amino acid tryptophan, which produces the typical indole ring [24], giving these compounds the name “indolealkylamines.” A compound’s chemical structure determines which receptors it can bind and activate, its absorption, distribution, metabolism and elimination and its effects. In fact, minor additions and modifications to the indolealkylamine backbone provide an endless supply of novel tryptamine structures, each with a unique pharmacology. Table 1 presents the most common and newest tryptamines and metabolites, with their common backbone structure and numerous ring substitutions. Tryptamines base structure is represented on Figure 1.

Figure 1. Tryptamines base structure.

Some tryptamine structures facilitate crossing the blood brain barrier, with a rapid onset of highly potent effects and other structures prevent rapid metabolic degradation, increasing the duration of effects [25]. Some tryptamines and derivatives are potent and short-acting psychedelics, whose total duration of action is less than thirty min [25]. Such compounds must be taken parenterally or enterally to experience the psychedelic effects. MAO is a mitochondrial flavin-dependent enzyme that oxidatively deaminates serotonin and other biogenic and neuroactive amines and is present in the liver, gut and brain of humans and other mammals. If tryptamines are orally ingested, protection from peripheral degradation by a monoamine oxidase inhibitor (MAOI) may be necessary for activity. Consequently, MAOI generally increases the pharmacological effects of such bioactive amines.

2.1. Tryptamines of Natural Origin

• Dimethyltryptamine (DMT)

DMT shares psychedelic and hallucinogenic activity with lysergic acid diethylamide (LSD) and mescaline in terms of intensity and characteristics [22]. Common routes of DMT administration are oral, insufflation, intravenous (IV) and smoking [24]. The time course of DMT administered via inhalation of vaporized freebase or IV injection of a water-soluble salt is brief. The onset is rapid, with full effects noted within 2 min of administration and subjective effects fully resolving within 20–30 min [25]. Szára et al. also reported a rapid onset (2–5 min) of effects and a duration of action of 30–60 min following intramuscular (IM) administration of 0.2–1 mg/kg DMT [26]. These authors reported that 0.7 mg/kg IM DMT resulted in diarrhea, nausea and vomiting. Additionally, elevated heart rate, blood pressure and rectal temperature were reported by others following DMT administration [27]. Psychologically, DMT can cause short-term emotional distress and in some cases precipitate long-lasting psychosis. DMT is an agonist at the 5-HT1A, 5-HT2A and 5-HT2C serotonin receptors and at the sigma-1 receptor. DMT’s broad agonist activity includes modulation of physiological processes and regulation of inflammation through the sigma-1 and 5-HT receptors and changing immune responses through the sigma-1 receptor. IM effects are usually less intense than those following IV or inhalation. Oxidative deamination of DMT by monoamine oxidase (MAO) produces indole-3-acetic acid (3-IAA) and 3-indole-aceturic acid [28]. Other metabolic pathways include N-oxidation, N-demethylation and cyclization. DMT-N-oxide (DMT-NO), N-methyltryptamine (NMT), 2-methyl-1,2,3,4-tetrahydro-beta-carboline (2-MTHβC) were also identified as minor DMT metabolites [28].

DMT was first isolated from Mimosa hostiles, Mimosa tenuiflora and Mimosa root bark and is also present in Psychotria viridis leaves and Virola plants, all parts of the beverage Ayahuasca [25]. Ayahuasca is produced by mixing different plants by native populations of the basin of the Amazon river, suggested to be a drink with magic and curative powers. For the decoction preparation, the natives boil the bark or crushed stems of Banisteriopsis caapi together with other plants, including the leaves of Psychotria viridis, a member of the Rubiaceae family. The two plants are distinguished by the content of active compounds. Psychotria viridis contains DMT and Banisteriopsis caapi contains harmala alkaloids (Peganum harmala or Syrian Rue) harmine, tetrahydroharmine and harmaline [29]. DMT is a hallucinogen and the harmala alkaloids are MAO inhibitors that enhance DMT’s effects. Ayahuasca is used to treat depression, anxiety and alcohol, tobacco [30] and drug addiction [31]. DMT is also found as a minor alkaloid in the bark, pods and beans of Anadenanthera peregrina and Anadenanthera colubrina [32].

In 2015, Paterson et al. [33] reported an acute intoxication in Los Angeles, California of an unknown amount of smoked DMT by a 42-year-old male with no psychiatric history other than multiple substance use disorders. He was on an involuntary legal hold for bizarre and disorganized behavior that ultimately led to his hospitalization. During the interview in the emergency department (ED), he reported smoking cannabis and three weeks before hospitalization, he began smoking DMT. The subject was agitated, underweight and exhibited a marked disorientation to time. The patient received supportive therapy, including sedation with benzodiazepines. After 21 days hospitalization, he was discharged without complications. The urine toxicology analysis was performed 5 days after ED admission and resulted positive only for benzodiazepines and negative for DMT.

In 2017, Bilhimer et al. [34] reported an acute intoxication involving DMT in the U.S. A 25-year-old male with a history of mental illness had strong hallucinations and suicidal thoughts after injecting DMT intravenously. The subject had dilated pupils, tachycardia (88 bpm) and systolic and diastolic blood pressure of 116/71 mm Hg. His urine was immunoassay positive for amphetamines and DMT at a concentration greater than 2000 ng/mL.

• Psilocybin and psilocin

Psilocybin (4-Phosphoryloxy-N,N-dimethyltryptamine) and psilocin (4-Hydroxy-N,N-dimethyltryptamine or 4-OH-DMT), are contained in about 190 species of Psilocybe mushrooms but the most well-known varieties are Psilocybe cubensis, Psilocybe semilanceata and Psilocybe Mexicana. Psilocybin is a 4-substituted indoleamine that is dephosphorylated to psilocin, its pharmacologically active metabolite [35]. Albert Hofmann [36] first isolated and identified psilocin from the Psilocybe Mexicana mushroom in 1958. Psilocybe cubensis contains the highest concentrations of these two tryptamines and is available frozen or as a dry powder or capsule [36]. In addition to its natural origin, synthetic psilocin is available fresh or treated/preserved (dried or cooked). Psilocin is highly unstable in solution and in the presence of oxygen and alkaline pH, it forms bluish and black degradation products. This tryptamine is an isomer of bufotenine, differing only in the position of the hydroxyl group [35]. Psilocin is orally active with a duration of action of 4–6 h [25]. Psilocin undergoes oxidative deamination and forms the minor metabolite 4-hydroxyindole acetic acid (4-HIAA). This tryptamine is also subject to phase II metabolism to the O-glucuronide, the main metabolite detected in human urine. In recent years, fungis’ sclerotia, commonly called “magic truffles,” frequently supply the psychoactive Psilocybe alkaloids, as Psilocybe sclerotia are not specifically included in the laws banning the sale, the purchase and the use of such substances [37]. Terms for magic truffles include The Philosopher Stones, Space truffles, Sclerotia Stones or Sclerotia. Psilocybin mushroom ingestion produces hallucinations as early as 10 min post ingestion of 1–2 mg dried mushrooms and typically lasts from 4–12 h. Common symptoms include dizziness, giddiness, nausea, weakness, muscle aches, shivering, anxiety, restlessness and abdominal pain [38,39]. In 2018, Honyiglo et al. described the death of an 18 year old male in France who jumped from the second floor and died following “hallucinogenic mushroom” intake [40]. The intoxication was confirmed by identification and quantification of psilocin in cardiac and femoral blood (67 and 60 ng/mL respectively), urine (2230 ng/mL), bile (3102 ng/mL) and vitreous humor (57 ng/mL). Gas chromatography time-of-flight detection with electron impact ionization (GC-EI-TOF) was the analytical technique employed for identification and quantification.
Currently, there is great interest in psilocybin in combination with psychotherapy to treat psychiatric disorders like anxiety, depression and addiction to nicotine and drugs [41,42]. For example, Grob et al. dispensed 0.2 mg/kg oral psilocybin, with a niacin placebo control to advanced-stage cancer patients with anxiety [43]. There was a significant reduction in anxiety at 1 and 3 months after treatment based on patients’ Speilberg State-Trait Anxiety Inventory (STAI). Carhart et al. [41] administered psilocybin to treat 12 patients with moderate-to-severe, unipolar, treatment-resistant major depression with two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. In addition, two randomized blinded controlled clinical trials demonstrated significant long-term reductions in anxious depressed mood after psilocybin treatment [42,44]. Essential distress also decreased and quality of life improved in terminally ill cancer patients after a single oral dose of psilocybin. An open-label pilot study provided psilocybin in combination with cognitive behavioral therapy to 15 treatment-resistant tobacco/nicotine-dependent smokers [45]. Smoking abstinence was observed in 67% of patients at follow-up, documenting that psilocybin was more effective than the most successful FDA-approved medication, varenicline [38]. Finally, a recent open-label pilot study investigated psilocybin for the treatment of 10 alcohol-dependent individuals, with alcohol use decreasing dramatically after the first psilocybin administration [46].

• 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT)

5-MeO-DMT is a natural tryptamine [25] that requires the presence of a MAOI to produce psychedelic effects [22]. 5-MeO-DMT is ingested but unpublished reports describe inhalation as a common mean of consumption with effects appearing within 60 sec and lasting 5–20 min [46]. Effects include auditory, visual and time perception distortions, emotional experiences, memory impairment, asthma (12%), high blood pressure (9%) and chronic fatigue syndrome (8%) [47]. There is also evidence that some people use 5-MeO-DMT for treating psychiatric conditions, including depression, anxiety, post-traumatic stress disorder and problematic substance use [47,48]. Tryptamine derivates like DMT, 5-OH-DMT and 5-MeO-DMT are metabolized by MAO-A that catalyzes an oxidative deamination forming IAA [49,50,51].

Brush et al. reported a poisoning related to 5-MeO-DMT and harmaline ingestion [22,52]. The victim was a 17 year old male found collapsed after insufflation of 15–20 mg 5-MeO-DMT. GC/MS analysis of urine only confirmed the presence of both harmaline and harmine. At ED admission, the patient had hypertension and tachycardia (186 bpm) and was hyperthermic (40.7 °C). After administration of 2.5 mg lorazepam, the symptoms began to resolve and the patient was discharged without complication.

Sklerov et al. described the death of a 25 year old white male found unresponsive in a national park following ingestion of 5-MeO-DMT. Toxicological analyses revealed the presence of 5-MeO-DMT in blood, urine, gastric contents, bile, kidney, brain and liver. Moreover, the heart blood sample contained DMT (0.02 mg/L), 5-MeO-DMT (1.88 mg/L), tetrahydroharmine (0.38 mg/L), harmaline (0.07 mg/L) and harmine (0.17 mg/L). The medical examiner pronounced the death as due to psychedelic amine intoxication [22,53].

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