The hallucinogenic world of tryptamines: an updated review

This review (2015) provides a comprehensive overview of a broad class of serotonergic hallucinogens known as tryptamines, concerning their evolution, prevalence, patterns of use and legal status, chemistry, toxicokinetics, toxicodynamics, and their physiological and toxicological effects on animals and humans. Although classical psychedelics are generally considered to be physiologically safe molecules, there is a lack of information on new tryptamine derivatives, regarding their acute and long-term effects, interactions with other substances, toxicological risk, or addictive potential.

Abstract

“Review: In the area of psychotropic drugs, tryptamines are known to be a broad class of classical or serotonergic hallucinogens. These drugs are capable of producing profound changes in sensory perception, mood and thought in humans and act primarily as agonists of the 5-HT_2A receptor. Well-known tryptamines such as psilocybin contained in Aztec sacred mushrooms and N,N-dimethyltryptamine (DMT), present in South American psychoactive beverage ayahuasca, have been restrictedly used since ancient times in sociocultural and ritual contexts. However, with the discovery of hallucinogenic properties of lysergic acid diethylamide (LSD) in mid-1900s, tryptamines began to be used recreationally among young people. More recently, new synthetically produced tryptamine hallucinogens, such as alpha-methyltryptamine (AMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), emerged in the recreational drug market, which have been claimed as the next-generation designer drugs to replace LSD (‘legal’ alternatives to LSD). Tryptamine derivatives are widely accessible over the Internet through companies selling them as ‘research chemicals’, but can also be sold in ‘headshops’ and street dealers. Reports of intoxication and deaths related to the use of new tryptamines have been described over the last years, raising international concern over tryptamines. However, the lack of literature pertaining to pharmacological and toxicological properties of new tryptamine hallucinogens hampers the assessment of their actual potential harm to general public health. This review provides a comprehensive update on tryptamine hallucinogens, concerning their historical background, prevalence, patterns of use and legal status, chemistry, toxicokinetics, toxicodynamics and their physiological and toxicological effects on animals and humans.”

Authors: Ana Margarida Araújo, Félix Carvalho, Maria de Lourdes Bastos, Paula Guedes de Pinho & Márcia Carvalho

Summary

The hallucinogenic world of tryptamines: an updated review

This review provides a comprehensive update on tryptamine hallucinogens, including their historical background, prevalence, patterns of use, legal status, chemistry, toxicokinetics, and toxicodynamics.

Introduction

In recent years, many new psychoactive substances have appeared on the drug market, including synthetic chemicals, plant or fungal materials, and herbal mixtures. These substances have similar pharmacological effects to the classical drugs of abuse, but are legal and cheaper.

Tryptamines are a broad class of classical or serotonergic hallucinogens that can produce profound changes in sensory perception, mood and thought in humans. They have been used in sociocultural and ritual contexts since ancient times, but have recently been used recreationally.

New psychoactive substances are sold in packages labeled ‘not for human consumption’, and are intentionally marketed as replacements for illegal drugs. These substances are created by modifying the molecular structure of controlled psychoactive molecules.

More than 300 new psychoactive substances have been synthesized since the beginning of the twenty-first century, including four new tryptamine derivatives in 2012. These substances may have hallucinogenic properties and have replaced the consumption of traditional hallucinogens.

There is little information available on these new tryptamine derivatives, which are rarely subject to studies in animals or humans. This paper gathers data on the chemical, pharmacological and toxicological properties of currently known tryptamine derivatives.

What is a hallucinogen? The definition

Hallucinogens are drugs that produce changes in thought, perception and mood without producing memory or intellectual impairment or addiction. They are also known as classical or serotonergic hallucinogens.

The evolution in the use of tryptamines: from natural substances to synthetic drugs

Nature produces compounds that have profound effects on the central nervous system. Humans have used these compounds since prehistory.

Ayahuasca is a hallucinogenic brew made out of Banisteriopsis caapi and Psychotria viridis, and is traditionally used in religious ceremonies and for therapeutic purposes. It contains considerable amounts of DMT and is believed to be effective in the treatment of abuse disorders and some physical maladies.

DMT is a hallucinogenic compound found in various plants, including Desmanthus illinoensis, Phalaris arundinacea, Phalaris aquatic, Mimosa hostilis and Phalaris tuberosa. It induces visual hallucinations, spatial distortions, speech disturbance and euphoria when administered intramuscularly in humans.

Psilocybe mushrooms contain tryptamine derivatives, which are thermostable and produce changes in perception and behavior. These mushrooms are used for recreational purposes in the UK and the USA.

Another known natural tryptamine is bufotenine, an N-alkylated derivative of serotonin and a structural isomer of psilocin. It is also present in hallucinogenic plants and can be synthesized in human pineal gland and urine.

Mankind has used consciousness-altering substances for millennia, but Western researchers have created new synthetic psychoactive substances that have gained prominent popularity in recreational drugs scenarios, resulting in their widespread propagation and abuse.

LSD is a synthetic hallucinogenic drug that was synthesized by Hofmann in 1938. Its consciousness-altering properties were discovered accidentally a few years later, and it was banned in 1966 and reclassified as a Schedule I controlled substance in 1970.

There are more hallucinogenic substances on the market than ever before, including AMT, 5-MeO-DIPT and DALT. AMT was developed in the Soviet Union in the 1960s as an antidepressant, while 5-MeO-DALT was introduced as a party drug in 1999.

The emergence of new ‘designer drugs’ and the void of information associated with them represent a public health issue. New legislative measures regarding ‘designer drugs’ have been introduced in several countries, including Portugal.

Designer drugs are often sold with creative packaging, presenting them as harmless and with minimal information about their composition. They are often sold to individuals aged 18 or older, although in practice this rule is not strictly enforced. Some tryptamines have characteristic properties, such as 5-MeO-DALT, a white to light brown powder with a slight smell. Several tryptamines can be purchased in Internet Web sites in small quantities or in substantial amounts. Prices can range from 17 to 29€ per gram up to thousands of euros per kg.

A study on the legal high products available in the UK online market in 2009 revealed that stimulants, sedatives and hallucinogens were the most popular products.

In 2009, psilocin was the most frequent natural product detected in urine specimens from young users admitted at emergencies. The subjects admitted to having acquired the products through the Internet.

A study performed by Maxwell (2014) revealed that tryptamine users tend to be young adults and male, and that this kind of consumption affects different races and ethnicities.

A global study of 22,289 subjects conducted online between November and December 2012 revealed that DMT is an increasingly popular substance for those looking for an alternative to traditional hallucinogens.

In Australia, 121 participants that used DMT at least once in their lifetime were surveyed. The median total number of DMT consumption per participant was ten times, preferably smoked.

Despite the worldwide prevalence of tryptamines being virtually unknown, their popularity has been increasing, and many factors can explain this phenomenon, including their availability and ease of acquisition, as well as their lower price compared to illicit classical drugs.

Chemistry

Hallucinogens can be divided into two main structural classes: phenylalkylamines and indolamines. Phenylalkylamines contain a phenethylamine group, while indolamines contain an indole nucleus, and share a high structural similarity with 5-hydroxytryptamine (5-HT).

Indolamines can be subclassified into two main groups: simple tryptamines and ergolines. Simple tryptamines have a bicyclical combination of benzene and a pyrrole ring, while ergolines have a complex and relatively rigid structure with an indole system and a tetracyclic ring.

Different structural modifications of tryptamine gave rise to diverse molecules with dissimilar chemical properties, which consequently have the ability to induce different states of mind and behaviors.

Alkyl-N-substituted tryptamines with longer chains are unaffected by MAO degradation, being orally active, but the potency is lower. Hydroxyl substitution in the indole ring can provide varied properties with some derivatives being hallucinogenic, while others may have no psychoactivity.

Routes of administration, typical doses and duration of effects

Psilocybe mushrooms users typically consume the mushrooms raw or prepare tea by steeping fresh or dry biomass in hot water, and synthetic tryptamines may be consumed by a set of known routes of administration.

User reports indicate that 4-OH-MET, 5-MeO-DIPT and 5-MeO-DALT can be administered orally or by intranasal route, while DMT is not orally active due to extensive first-pass metabolism.

DMT can be consumed orally, but some users use MAO inhibitors to enhance the activity of DMT. However, some MAO inhibitors are neurologically active too, and some tryptamines are converted to substitutes -carboniles in the human body.

The dose of tryptamine derivatives depends on their potency and route of administration. The presence of a 4-hydroxy or a 5-methoxy substituent on the indole ring increases their potency.

Psilocybin is 45 times less potent than LSD, and the typical oral dose per adult is above 15 or 1 – 2 mg when administered intravenously (i.v.). The effects begin to occur 20 – 40 min after oral administration, and last 4 – 6 h.

5-MeO-DALT and 4-OH-MET have dose dependent effects, with the onset of effects around 15 min and duration of action between 2 and 4 h, although the visual disturbance may persist for a longer period.

Ayahuasca’s hallucinogenic effects usually appear within 1 h after its oral consumption and can last about 4 h. DMT’s effects are intense and emerge rapidly but last 30 min, in contrast to LSD’s long duration of effects (8 – 12 h).

Metabolic pathways

A limited number of studies have been performed on the metabolism of indolamine hallucinogens, including LSD, psilocybin, DMT, 5-MeO-DMT and 5-MeO-DIPT. It is suggested that not all tryptamines share a common metabolic pathway, varying upon the nature and position of substituents in the molecules.

LSD in urine is metabolized to several different compounds, including 2-oxo-LSD, 2-oxo-3-hydroxy-LSD, N-desmethyl-LSD, 13- and 14-hydroxy-LSD glucuronides, and the main metabolite, 2-oxo-3-hydroxy-LSD, which is formed through dehydrogenation of the 2,3-dihydroxy-LSD intermediate.

Psilocybin is rapidly dephosphorylated by phosphatases in the digestive tract, in kidney and probably in the human blood to generate its pharmacologically active metabolite psilocin, which is further metabolized by phase II enzymes to give the psilocin-O-glucuronide.

DMT, 5-OH-DMT and 5-MeO-DMT are extensively metabolized through oxidative deamination to their corresponding indole acetic acid (IAA) derivatives mediated by monoamine oxidase A (MAO-A). DMT-N-oxide (DMT-NO) is found in significant concentrations in the human urine and blood following oral administration of ayahuasca.

DMT is metabolized to IAA, NMT, 2-MTHBC, and THBC. 5-MeO-DMT is metabolized by essentially the same routes as described for DMT, and the MAO-dependent metabolite, 3-IAA, represents 97 % of the recovered compounds after oral ingestion of DMT alone and in ayahuasca preparation.

Ayahuasca inhibits MAO, but only partially, and the presence of -carbolines in ayahuasca is sufficient to allow drug central effects. Smoked DMT also exhibits psychoactive effects, and unmetabolized DMT is found in urine together with around 63 % IAA and 28 % DMT-NO.

The metabolism of 5-MeO-DIPT (‘foxy’), a recently abused tryptamine derivative, was recently characterized in urine samples from users. The hydroxylated metabolites were detected in greatest abundance and may still undergo phase II reactions, being partially eliminated as sulfate or glucuronide conjugates. In vivo studies performed in rats revealed a similar metabolic profile to that observed in humans, with 5-hydroxy-N-isopropyltryptamine (5-OH-NIPT) being the main metabolite. In vitro studies using rat liver microsomes revealed different CYP enzymes involved in 5-MeO-DIPT rat metabolism.

Receptor interactions

The discovery of serotonin in the brain occurred in 1953, and the synthesis of LSD was accomplished in 1968. It was quickly noticed that these two substances had similar effects, and that LSD stimulated central 5-HT receptors.

Despite their chemical differences, phenylalkylamine and indolamine hallucinogens produce similar effects in animals and humans, and both act through the same receptors. The affinity of phenylalkylamines to 5-HT2 receptors correlates with hallucinogenic potency in humans.

Different 5-HT1 and 5-HT2 receptor subtypes bind to different compounds with different affinities, such as N1-n-propyl-5-methoxy–methyltryptamine binding preferentially to 5-HT2 receptors and 5-MeO-DIPT binding to 5-HT1A and 5-HT2C receptors.

Tryptamine derivatives bind to and activate serotonin 5-HT2A receptors, although many bind to and activate non-serotonergic receptors as well. DMT is also a ligand to the trace amine-associated receptors (TAAR) and the vesicular monoamine transporter 2 (VMAT2) and serotonin transporter (SERT).

Behavioral and physiological studies in animals

Although few human clinical trials using hallucinogenic drugs have been conducted, animal behavior models have been the main methodology used to study their effects in vivo. The drug discrimination paradigm is a valuable tool to study the activity of psychoactive drugs. Drug discrimination studies in rats showed that DMT and DIPT produce predominately hallucinogenic-like discriminative stimulus with minimal psychostimulant effects, while DOM, LSD and MDMA failed to substitute for the discriminative stimulus.

Hallucinogens activate 5-HT2A receptors in brain, and several behavioral paradigms have been used to evaluate the effects of hallucinogens. These studies have shown that 5-HT2A receptors are the main target of 5-HT2C/2B antagonists.

Abnormal behaviors and increased impulsiveness have been described after consumption of tryptamine hallucinogens. These behaviors are compromised in 5-HT2A / knockout mice, reinforcing the involvement of 5-HT2A receptors to this behavior.

Additional behavioral studies revealed that DMT and 5-MeO-DMT inhibit rats fighting at higher doses but not at lower doses, whereas LSD facilitates the fighting at low doses but does not produce effects at high doses.

When testes with tryptamines in a novel environment, a decreased locomotor activity and exploratory behaviors and increased avoidance of the center region are observed, whereas these effects are not observed when testes with tryptamines in a familiar location.

AET produced a behavior profile that was extremely similar to that of MDMA, and was attenuated by pretreatment with fluoxetine. 5-MeO-DMT produced a late hyperactivity that was completely blocked by the 5-HT2A antagonist MDL 11,939 but unaffected by WAY-100635.

Additional studies demonstrated that rats treated with 5-MeO-DIPT during adolescence showed deficit in certain cognitive tasks, but were able to master the spatial navigation tests similar to control rats. However, 5-MeO-DIPT did not affect the rats’ ability to perform novel object or place recognition tasks.

Experimental studies were performed on rats and rabbits to evaluate the influences of tryptamine derivatives on thermoregulation. The results showed that some compounds had no effect on the evaluated parameters, while others induced only behavioral alterations, and most of them produced significant effects in both parameters.

Subjective effects and adverse reactions in humans

Hallucinogens in humans have subjective and hard to assess effects, but in general, the hallucinogenic effects overrule the stimulant effects. Alpha-methylated tryptamines have stimulant properties, but the visual hallucinations predominate at higher doses.

Hallucinogens are capable of producing complex mental and perceptual alterations, and can cause ataxia, hyperreflexia, clonus, severe agitation, psychosis, paranoia, delusions, confusion, excited delirium, echolalia, anterograde amnesia and catalepsy. Tryptamine derivatives can also induce panic reactions and prolonged psychotic or depressive reactions.

Tryptamines have short duration in humans, which could lead to a repeated consumption resulting in an elevated risk of subsequent tryptamine dependence. However, DMT consumption does not seem to translate into a greater boost to consumption.

The consumption of synthetic tryptamines has been associated with fatal cases in recent years. One death was caused by the ingestion of 5-MeO-DIPT (‘foxy’), which was detected in postmortem fluids at concentrations higher than those published in other cases of ‘foxy’ intoxications.

Concomitant exposure to tryptamines and MAO inhibitors can have serious consequences, including hyperserotonergic effects or serotonin toxicity.

A young student died after consuming AMT, which caused severe agitation and visual hallucinations. Toxicological analyses revealed high levels of AMT in his blood, gastric content, liver and brain tissues.

A young male snorted 350 mg of 5-MeO-DALT purchased via the Internet and was seen to walk out into the slow lane of a motorway, possibly as a result of its hallucinogenic state.

Tryptamines intoxication can be treated with supportive therapy targeted specifically to the symptoms observed, and a combination of supportive care and sedation. Activated charcoal may be useful after oral exposure, but has limited efficacy after insufflation or smoking.

Concluding remarks

Tryptamines are hallucinogens that act on the serotonin 5-HT2A receptor. New tryptamine derivatives have been replacing traditional hallucinogens, but there is very little information available concerning their acute and long-term effects, their possible interactions with other substances, their toxicological risks or even their addictive potential.

Research on synthetic tryptamines is fully required in order to access their actual potential hazard. This manuscript provides a comprehensive update on these drugs, concerning their evolution, prevalence, patterns of use and legal status.