Recreational Use, Analysis and Toxicity of Tryptamines

This comprehensive review (2015) summarizes the chemical characterization, pharmacology, and toxicity of New Psychoactive Substances from the published literature, as well as information gathered from non-peer-reviewed sources, such as drug forums. They provide an overview of useful information, such as reported death cases, for public health workers.

Abstract

“Introduction: The definition New psychoactive substances (NPS) refers to emerging drugs whose chemical structures are similar to other psychoactive compounds but not identical, representing a “legal” alternative to internationally controlled drugs. There are many categories of NPS, such as synthetic cannabinoids, synthetic cathinones, phenylethylamines, piperazines, ketamine derivatives and tryptamines. Tryptamines are naturally occurring compounds, which can derive from the amino acid tryptophan by several biosynthetic pathways: their structure is a combination of a benzene ring and a pyrrole ring, with the addition of a 2-carbon side chain. Tryptamines include serotonin and melatonin as well as other compounds known for their hallucinogenic properties, such as psilocybin in ‘Magic mushrooms’ and dimethyltryptamine (DMT) in Ayahuasca brews.

Aim: To review the scientific literature regarding tryptamines and their derivatives, providing a summary of all the available information about the structure of these compounds, their effects in relationship with the routes of administration, their pharmacology and toxicity, including articles reporting cases of death related to intake of these substances.

Methods: A comprehensive review of the published scientific literature was performed, using also non peer-reviewed information sources, such as books, government publications and drug user web fora.

Conclusions: Information from Internet and from published scientific literature, organized in the way we proposed in this review, provides an effective tool for specialists facing the emerging NPS threat to public health and public security, including the personnel working in Emergency Department.”

Authors: Roberta Tittarelli, Giulio Mannocchi, Flaminia Pantano & Francesco Saverio Romolo

Summary

INTRODUCTION

New psychoactive substances (NPS) are defined as substances of abuse that are not controlled by the 1961 Single Convention on Narcotics Drugs or the 1971 Convention on Psychotropic Substances. They are formulated as “bulk powders, liquids, tablets, capsules, blotters” or herbal preparations.

The Internet is a growing source of on-line drug trafficking, with users often unaware of what or how much they are taking. The use of synthetic drugs has increased dramatically in recent years.

Tryptamines are monoamine alkaloids synthesized by decarboxylation of the aminoacid tryptophan. They can be found in plants, fungi, animals, microbes and amphibia.

The tryptamines play a fundamental role in human life, and are present in the ‘Magic mushrooms’ belonging to the Psilocybe cubensis species. These mushrooms contain psilocybin and psilocin, which show marked similarities with serotonin.

Chemical modifications of the nucleus structure of the tryptamine molecule produce new compounds that may cause alterations of the physical and mental status, ranging from toxic substances to anti-migraine drugs, such as Sumatriptan, Rizatriptan and Zolmitriptan.

-methyltryptamine (5-MeO-AMT)], being the presence of an alpha carbon methyl group, a characteristic in common with amphetamine. They are not routinely detected with common screening panels, so far in emergency rooms the test could result completely negative.

CLASSIFICATION OF TRYPTAMINES BASED ON THEIR CHEMICAL STRUCTURES

Several classifications have been suggested for these substances, including simple tryptamines, ergolines, and tryptamines with modifications on the indole ring.

RING UNSUBSTITUTED COMPOUNDS

Several compounds belong to this class, including -methyltryptamine (AMT, street name Spirals) and -ethyltryptamine (AET), both showing stimulant activities. AMT is active after oral administration, and inhibits MAO activity in vitro and in vivo.

Designer drugs on monoamine neurotransmission were studied using rat brain synaptosomes. AMT and 5-MeO-AMT were found to have the strongest effect on monoamine re-uptake inhibition and release stimulation. Illegal use of -methyl-tryptamine is based on its hallucinogenic and psychedelic visual effects, and can last up to 2 days. It can cause uncomfortable feelings such as restlessness, irritability, hyperthermia, anorexia, vomiting, inability to sleep, tachycardia, increase in blood pressure pupils dilatation, deep tendon reflexes and coordination impairment.

In the US, -methyltryptamine is a schedule I substance, while in the UK it was legal until June 2014. It caused 4 deaths from January to December 2012.

Alpha-ethyltryptamine (AET) was first introduced as an antidepressant agent by Upjohn company in 1960s, but was withdrawn from the market because of an unacceptable incidence of idiosyncratic agranulocytosis. AET induces serotonin neurotoxicity, similar to that of MDMA and para-chloroamphetamine (PCA), and is orally active.

DMT is a psychoactive compound that is synthesized from tryptamine and is found in many plants, animals, and mammals. DMT binds several serotonin receptors, including 5-HT2A and 5-HT2C, as well as 1-adrenergic receptors, dopamine D1, and sigma-1. Its psychedelic effects are probably due to the activation of 5-HT2A receptor. DMT can be taken orally, intravenously or by inhalation. It is deaminated by monoamine oxidase and is quickly inactivated, and must be associated with a MAOI if orally administered.

Diethyl-tryptamine (DET) is not found naturally and is active when administered orally. Its mechanism of action is not clear, but it may present an agonist activity towards serotonin receptors.

Dipropyl-tryptamine (DPT) was firstly synthesized in the 1950s, but it was first reported for use in the scientific literature only in 1973. It is found either as its crystalline hydrochloride salt or as an oily or crystalline base, and its psychoactive effects last for 2 to 4 hours.

Diisopropyl-tryptamine (DiPT) is a synthetic hallucinogen that produces auditory distortions. It is an agonist at 5HT2A receptors and a partial agonist at 5HT1A receptors, but 5-HT1A activity is not thought to be necessary for hallucinogenic effects.

4-POSITION MODIFIED TRYPTAMINES

Psilocin (4-OH-DMT) is the active drug of abuse obtained by dephosphorylation in the body of psilocybin found in hallucinogenic mushrooms of the species Psilocybe and Stropharia. The threshold of intoxication is reached after the intake of 40 g psilocybin/kg body weight. Psilocybin is a partial 5HT2a agonist, but it is also agonistic at other serotonin receptors, with little dopaminergic or noradrenergic action. It causes sympathetic stimulations, such as tachycardia and hypertension, along with the predominant hallucinogenic effects.

5 POSITION MODIFIED TRYPTAMINES

Bufotenine, an N-alkylated derivative of serotonin, was first synthesized by Wieland in 1934 and was found in plants, mushrooms and the skin glands of toads. It was rapidly eliminated from the body and was metabolized by MAO-A through the pathway of oxidative deamination.

Ott self administered bufotenine as free base via intranasal, sublingual, intrarectally, pulmonary (as inhaled vapor, in a dosage of 2 – 8 mg) and orally. He reported the onset of several psychoactive effects.

A psychedelic tryptamine with structural similarities to the amphetamines, 5-MeO-AMT was occasionally sold under the guise of LSD. Its sympathomimetic effects have caused several hospital admissions and sudden deaths.

5-MeO-DMT is a naturally occurring psychoactive indolealkylamine substance, closely related to DMT and bufotenine, which causes psychedelic effects with a short duration in humans.

5-MeO-DMT is metabolized by MAO-A and CYP2D6 and produces bufotenine, which binds to 5-HT2A receptor with higher affinity than 5-MeO-DMT itself. This causes an hyperserotonergic syndrome if used concomitantly with a MAOI.

Ott’s self-experiments revealed that 5-MeO-DMT caused visionary and auditory changes, with a distortion of the perception of time, lasting until 60-70 minutes.

5-MeO-DiPT is a competitive serotonin transporter (SERT) inhibitor and has an inability to cause reverse transport, underlying its serotonergic actions. It can cause psychotic effects in humans, such as euphoria, disinhibition, increased sociability, visual and auditory hallucinations, feeling of love, but also less desiderable effects like nausea, vomiting and diarrhea.

5-MeO-DALT was first synthesized by Shulgin and was first sequestered as two grey tablets, in 2006 at Helsinki airport. It has little scientific literature and is taken orally or nasally and causes euphoria, visual hallucinations, walking difficulties, and ‘out of body’ experiences.

5-MeO-MiPT is an analogue of 5-MeO-DiPT (Foxy), and suppresses the re-uptake of 5-HT, dopamine and norepinephrine.

5-MeO-MiPT can be smoked or taken orally. Its effects last from 4 to 6 hours and can cause euphoria, increased tactile sensations, relaxation, visual distortions and difficulty in sleeping.

ERGOLINES: HAWAIIAN BABY WOODROSE AND MORNING GLORY SEEDS

Ergine, an alkaloid of the ergoline family closely related to LSD, is found in the seeds of Argyreia nervosa and Ipomoea violacea. It has hallucinogenic activity and can cause relaxations, mild euphoria, feelings similar to alcohol intoxication, psychedelic visual effects, but also anxiety, nausea, confusion and paranoia.

EFFECTS DUE TO ASSUMPTION OF TRYPTAMINES REPORTED ON INTERNET

The effects of tryptamines are reported from websites, and are the result of personal experiences of authors. There are many risks associated with the possibility of overdose, repeated administration and incorrect route of administration.

DMT is a tryptamine that is not active after oral ingestion due to extensive first pass metabolism via MAO. Users report experiencing intense visual hallucinations, increased mood, energy, libido, concentration and empathogenic qualities when using DMT.

Synthetic 4-substituted tryptamines are orally active and seem to produce similar effects to those mediated by psilocin.

TRYPTAMINES

Users report similar clinical effects among 5-substituted simple tryptamines, including euphoria, an increasing of energy, libido, concentration and sociability, and a reduction in fear and anxiety.

User reports of adverse effects of unsubstituted tryptamines include restlessness, yawning, anxiety, tension, nausea, vomiting, palpitations, muscle pain, bruxism, headache, frightening or distressing hallucinations, overwhelming fear, abdominal discomfort, nasal irritation when insufflated and respiratory discomfort or distress when inhaled.

TRYPTAMINES EFFECTS AND INTOXICATIONS: CASE REPORTS FROM EMERGENCY ROOMS AND CORONERS’ ACTIVITIES

Data on the use of these new psychoactive substances is very difficult to gather, because they are not collected in a systematic way and often these information come from unverified sources. However, a consistent number of cases of acute poisoning due to the increasingly wide spread use of these substances is reported.

A college student, 21 years old, ingested 270 mg of AMT and presented with hypertension, apyrexia, moderate tremor, delay in response times, restless, in exaggerated startle reaction and visual hallucinations. The symptoms began to resolve after 10 hours.

A male patient with sympathomimetic effects after ingestion of AMT was found almost completely naked, while ran, and cried, and was immediately sedated with 6 mg lorazepam administrating by intramuscular route. Routine laboratory tests were normal, as well as the analysis of the cerebrospinal fluid and brain scan.

A 19 years old female presented with hallucinations, extreme agitation and tachycardia after ingesting an unknown amount of DPT. She was administered 3 mg of lorazepam to resolve the state of agitation.

An adolescent purchased Syrian rue seeds containing harmaline on the Internet, smoked 10 mg of 5-MeO-DMT, and inhaled further 15-20 mg, which led to severe poisoning. He required physical restraint and 2.5 mg of IV lorazepam.

A 23-year-old man had paranoia symptoms after ingestion of a 5-MeO-DiPT homemade capsule. Toxicological analysis revealed the presence of 5-MeO-DiPT in blood and urine.

A 23 years old man presented with altered state of consciousness, tachycardia, hypertension and hyperpyrexia after consuming 25 mg of 5-MeO-DiPT. Clinical investigations revealed renal impairment, metabolic acidosis and rhabdomyolysis.

A 19 years old man had hallucinations, hypertension, tachycardia, mydriasis, and catalepsy after ingesting an unusual dose of “Foxy”. His symptoms were resolved after administration of lorazepam.

A 21-year-old man arrived at the Emergency Department after consuming a capsule to get high, named “Foxy”, and was found to have 5-MeO-DiPT in his urine. He was also found to have codeine, nicotine, cotinine, acetaminophen, caffeine, and two other peaks that were assumed to be 5-MeO-DiPT metabolites.

41 exposures to “Foxy” were found in the AAPCC TESS database, with symptoms including agitation, hallucinations, tachycardia, hypertension, and confusion.

A 27-year-old Japanese businessman took a mixture of methylone and 5-MeO-MiPT to solve his sleep irregularities, but found out that it was composed of about 60% methylone and 38% 5-MeO-MiPT. He felt nausea and sick in the stomach for thirty minutes. A man was admitted to hospital after taking cocaine. He showed signs of psychomotor excitement and was shouting without apparent reason, but he did not remember anything of what happened during acute intoxication.

A 20-year-old college student was brought to the emergency department after ingesting a dietary supplement capsule that contained the novel synthetic tryptamine 5-MeO-DALT in unknown concentration. He was treated with benzodiazepines and haloperidol and was later discharged without symptoms or psychiatric sequelae.

FATALITIES INVOLVING TRYPTAMINE MISUSE

Tryptamines may be associated with a higher risk of overdose, because the information on these compounds available on the Internet is exclusively based on first-hand personal accounts.

In February 2003, a 22 years old college student was found deceased, 12 hours after confiding to his roommate he was “taking hallucinating drugs”. Postmortem toxicological analysis revealed the presence of AMT in the following concentrations (Table 9) .

Several deaths have been attributed to AET, a compound strictly related to -methyltryptamine, which was originally developed as an antidepressant.

A 19 years old female had a cardiac arrest after ingesting two ‘hits’ of white powder that she described as MDMA. AET was found in her blood, urine, vitreous, bile, and stomach contents, but no MDMA was revealed in autoptical samples.

A 25 years old white male was found dead in 2005 after consuming a herbal hallucinogenic extract. An autopsy was performed the day after the body was discovered and no anatomic cause of death was found. Toxicological analysis of specimens collected at autopsy revealed the presence of hallucinogenic amines in the heart blood and urine, as well as tetrahydroharmine and harmaline. Tetrahydroharmine was present in higher amounts than harmaline and harmine in all samples with the exception of the gastric contents.

Tanaka reported a fatal case of intoxication with “Foxy”, where a 29-year-old male suffered acute cardiac failure due to neurotoxocity resulting from an overdose of 5-MeO-DiPT. The cause of death was hypothesized to be a 100 mg dose, while a normal dose would be 10 mg.

A 26 year old male was killed after walking onto the slow lane of a motorway and being hit by a lorry. He had snorted 350 mg of 5-MeO-DALT and had a significant head injury.

A toxicological investigation found that the postmortem femoral blood contained an atracurium breakdown product (laudanosine) and propofol, which presence is consistent with medical intervention. A compound with a distinctive tryptamine-like UV spectrum was detected, but no other drugs were detected.

ANALYTICAL METHODS FOR TRYPTAMINES

Tryptamines are not routinary detected with common immunoassay-based techniques, and extensive laboratory analysis is required for their identification. However, even using powerful instrumentations, the new substances could be missed, either because reference mass spectra are not yet included in libraries, or because the fragments generated during the analysis show nondescript patterns.

Different extraction methods and sample preparation procedures were proposed for whole blood, serum, plasma and urine, while several biological matrices were investigated for forensic purposes. The separation techniques used were gas chromatography and High Performance Liquid Chromatography.

Several analyzers were used, including a quadrupole ion trap, a triple quadrupole, a high resolution Orbitrap, and a TOF analyzer with MALDI ionization system.

Results of analysis of substances seized from law enforcement agencies are published too, resulting in a useful source of information for specialists, including the personnel working in Emergency Departments.

CONCLUSIONS

Many psychoactive substances belong to the chemical class of tryptamines, and some are emerging drugs whose chemical structures are similar to other psychoactive compounds but not identical. The comprehensive review of the published literature permitted to find useful information from non peer-reviewed sources, including media reports and Internet resources.

This review provides a useful tool for forensic scientists and emergency department personnel facing this emerging threat.